High-linear energy transfer (LET) alpha versus low-LET beta emitters in radioimmunotherapy of solid tumors: therapeutic efficacy and dose-limiting toxicity of 213Bi- versus 90Y-labeled CO17-1A Fab' fragments in a human colonic cancer model.
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Recent studies suggest that radioimmunotherapy (RIT) with high-linear energy transfer (LET) radiation may have therapeutic advantages over conventional low-LET (e.g., beta-) emissions. Furthermore, fragments may be more effective in controlling tumor growth than complete IgG. However, to the best of our knowledge, no investigators have attempted a direct comparison of the therapeutic efficacy and toxicity of a systemic targeted therapeutic strategy, using high-LET alpha versus low-LET beta emitters in vivo. The aim of this study was, therefore, to assess the toxicity and antitumor efficacy of RIT with the alpha emitter 213Bi/213Po, as compared to the beta emitter 90Y, linked to a monovalent Fab' fragment in a human colonic cancer xenograft model in nude mice. Biodistribution studies of 213Bi- or 88Y-labeled benzyl-diethylene-triamine-pentaacetate-conjugated Fab' fragments of the murine monoclonal antibody CO17-1A were performed in nude mice bearing s.c. human colon cancer xenografts. 213Bi was readily obtained from an "in-house" 225Ac/213Bi generator. It decays by beta- and 440-keV gamma emission, with a t(1/2) of 45.6 min, as compared to the ultra-short-lived alpha emitter, 213Po (t(1/2) = 4.2 micros). For therapy, the mice were injected either with 213Bi- or 90Y-labeled CO17-1A Fab', whereas control groups were left untreated or were given a radiolabeled irrelevant control antibody. The maximum tolerated dose (MTD) of each agent was determined. The mice were treated with or without inhibition of the renal accretion of antibody fragments by D-lysine (T. M. Behr et al., Cancer Res., 55: 3825-3834, 1995), bone marrow transplantation, or combinations thereof. Myelotoxicity and potential second-organ toxicities, as well as tumor growth, were monitored at weekly intervals. Additionally, the therapeutic efficacy of both 213Bi- and 90Y-labeled CO17-1A Fab' was compared in a GW-39 model metastatic to the liver of nude mice. In accordance with kidney uptake values of as high as > or = 80% of the injected dose per gram, the kidney was the first dose-limiting organ using both 90Y- and 213Bi-labeled Fab' fragments. Application of D-lysine decreased the renal dose by >3-fold. Accordingly, myelotoxicity became dose limiting with both conjugates. By using lysine protection, the MTD of 90Y-Fab' was 250 microCi and the MTD of 213Bi-Fab' was 700 microCi, corresponding to blood doses of 5-8 Gy. Additional bone marrow transplantation allowed for an increase of the MTD of 90Y-Fab' to 400 microCi and for 213Bi-Fab' to 1100 microCi, respectively. At these very dose levels, no biochemical or histological evidence of renal damage was observed (kidney doses of <35 Gy). At equitoxic dosing, 213Bi-labeled Fab' fragments were significantly more effective than the respective 90Y-labeled conjugates. In the metastatic model, all untreated controls died from rapidly progressing hepatic metastases at 6-8 weeks after tumor inoculation, whereas a histologically confirmed cure was observed in 95% of those animals treated with 700 microCi of 213Bi-Fab' 10 days after model induction, which is in contrast to an only 20% cure rate in mice treated with 250 microCi of 90Y-Fab'. These data show that RIT with alpha emitters may be therapeutically more effective than conventional beta emitters. Surprisingly, maximum tolerated blood doses were, at 5-8 Gy, very similar between high-LET alpha and low-LET beta emitters. Due to its short physical half-life, 213Bi appears to be especially suitable for use in conjunction with fast-clearing fragments. (+info)
Treatment of H. pylori infection: the reality.
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Despite the wide dissemination of information on Helicobacter pylori, there is still a great deal of variation in how general practitioners treat the infection and in which circumstances they prescribe eradication therapy for H. pylori. Specialty societies have developed consensus guidelines that recommend a strategy to test and treat dyspeptic patients for H. pylori infection although the data to support these recommendations are weak at the present time. As a result, there is still confusion about the indications for treatment and the treatment regimens that are likely to be effective in routine clinical practice. (+info)
Bismuth-mediated disruption of the glycocalyx-cell wall of Helicobacter pylori: ultrastructural evidence for a mechanism of action for bismuth salts.
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The mechanism of bismuth's bactericidal activity against Helicobacter pylori was investigated using transmission electron microscopy (TEM) and analytical electron microscopy (AEM); time-kill kinetic methods evaluated the effect of excess divalent cations. TEM analysis of untreated H. pylori revealed a normal morphology. In contrast, H. pylori exposed to bismuth salts had swollen, distorted cells with membrane-cell wall blebbing and a cytoplasm containing electron-dense, sometimes crystalline aggregates. By AEM, swollen cells contained bismuth at the cell periphery, whereas bacillary forms contained cytoplasmic bismuth localizations. Time-kill studies showed that the bactericidal activity of bismuth could be prevented by pretreatment with divalent cations. The effects of bismuth salts on the glycocalyces-cell walls of H. pylori with reversal of bactericidal activity by divalent cations are identical to those produced by other polycationic agents on various gram-negative bacilli. We conclude that disruption of the glycocalyces-cell walls of H. pylori is one mechanism of action for bismuth salts. (+info)
Effects of ranitidine bismuth citrate on Helicobacter pylori motility, morphology and survival.
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AIM: The effects of the anti-ulcer agents ranitidine bismuth citrate (RBC), ranitidine hydrochloride (R) and colloidal bismuth citrate (BC), on Helicobacter pylori motility, morphology and survival were examined to determine whether the clinical effectiveness of RBC might be linked to a specific action that inhibits bacterial motility. METHODS: H. pylori from patients with duodenal ulcer or non-ulcer dyspepsia were exposed to RBC and BC at bismuth concentrations ranging from 12.5 to 50 microg/mL, and R at ranitidine concentrations ranging from 12.5 to 50 microg/mL for a brief period (< 15 min), 6 h and 24 h. Bacterial motility was assessed with a Hobson BacTracker, bacterial morphology by transmission electron microscopy, and growth inhibition by counting colony-forming units. RESULTS: H. pylori motility was diminished with RBC and BC but not R. However, the effect of RBC was markedly greater than that of BC at each bismuth concentration and time of exposure tested: (i) brief exposure to RBC/bismuth 50 microg/mL but not to BC, resulted in a significant loss of motility without loss of viability or change in cell morphology, and (ii) bacteria were immobilized, and lost viability after exposure to RBC/bismuth 50 microg/mL for 24 h but not to BC. Morphological destruction caused by RBC differed from that by BC: after 24 h exposure to the highest concentration tested, cell fragmentation and flagella detachment occurred more frequently with BC than RBC, but the latter produced greater disruption of intracellular structures. CONCLUSIONS: RBC suppresses growth of H. pylori, and has a specific inhibitory effect on the bacterial motor mechanism. These pharmacological actions are likely to contribute to the clinical effectiveness of the agent. (+info)
Evaluation of treatment regimens to cure Helicobacter pylori infection--a meta-analysis.
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OBJECTIVE: To assess effectiveness of treatment to cure Helicobacter pylori infection. DATA SYNTHESIS: Meta-analysis of 666 manuscripts (full papers, abstracts, letters to the editor) identified through Medline and a manual search (1986 to January 1998). Data were overviewed by regression analysis with weighted random effects models. SUBJECTS: 53 228 patients with H. pylori infection. INTERVENTIONS: Patients were treated with 132 different medication combinations. MAIN OUTCOME MEASURE: Cure of H. pylori infection per protocol and intention-to-treat basis at least 28 days after treatment. RESULTS: The nationality of the patients and therapeutic regimen have a significant impact on the results, after correction for the heterogeneity in the precision of the cure rate caused by different study sizes and random effect for study. On the basis of the original sample size, cure rates of 80-85% were achieved using combinations of a proton-pump inhibitor or ranitidine bismuth citrate with two antibiotics including clarithromycin, amoxycillin and metronidazole or tinidazole. Comparable cure rates were also achieved using a combination of a proton-pump inhibitor or H2-receptor antagonist with bismuth subcitrate or tripotassium dicitrato bismuthate, metronidazole and tetracycline. The dose of clarithromycin influenced cure rates. Treatment duration did not influence the outcome. CONCLUSION: Several therapeutic regimens are eligible to cure H. pylori infection. However, none of the medication combinations were able to cure H. pylori infection in more than 85% of the patients assessed by intention-to-treat. The countries in which the studies were performed also had a significant impact on eradication rates. (+info)
Comparison of two 3-day Helicobacter pylori eradication regimens with a standard 1-week regimen.
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BACKGROUND: The duration of Helicobacter pylori eradication regimens has decreased to 1 week with cure rates of over 90%. This can be attributed to the use of triple drug regimens including potent inhibitors of gastric acid secretion and clarithromycin. There is no theoretical reason why shorter regimens should not be possible. AIM: To compare two 3-day, low-dose, twice daily regimens with 1 week of omeprazole 20 mg b.d., clarithromycin 250 mg b.d., and metronidazole 400 mg b.d. (OCM) METHODS: Outpatients referred for gastroscopy were screened by biopsy urease test. H. pylori-positive patients were randomized to receive either lansoprazole 30 mg b.d., tri-potassium dicitrato bismuthate one tablet b.d., clarithromycin 250 mg b.d., and amoxycillin 1 g b.d. for 3 days (LTdbCA), or ranitidine bismuth citrate 400 mg b.d., clarithromycin 250 mg b.d. and amoxycillin 1 g b.d. for 3 days (RbcCA) or omeprazole 20 mg b.d., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. for 1 week (OCM). They were not pre-treated with a gastric acid inhibitor. After 8 weeks, H. pylori status was assessed by 13C urea breath test. RESULTS: 974 out of 1114 patients referred for gastroscopy were screened by biopsy urease test. 140 patients were not screened either because they were anticoagulated or for technical reasons. 334 patients were H. pylori-positive: 154 were excluded mostly because of allergy to penicillin and personal reasons but 180 were randomized to treatment All regimens were well tolerated. For LTdbCA (n=60), RbcCA (n=59), and OCM (n=61) the H. pylori cure rates (95% CI) were 23% (12-34), 14% (5-23) and 87% (79-95), respectively, using intention-to-treat analysis and 25% (14-36), 15% (6-24) and 88% (80-96), respectively, if analysed per protocol. OCM was significantly superior to LTdbCA and RbcCA (P < 0.001) but there was no significant difference between regimens LTdbCA and RbcCA. CONCLUSIONS: OCM is an extremely effective H. pylori eradication regimen. The 3-day regimens tested both have poor cure rates. Pre-treatment with a proton pump inhibitor, higher doses or more frequent dosing may be necessary to increase the cure rate of short duration regimens. However, this could make them less acceptable than the H. pylori eradication regimens currently available. (+info)
Effect of ranitidine bismuth citrate on the phospholipase A2 activity of Naja naja venom and Helicobacter pylori: a biochemical analysis.
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BACKGROUND: Helicobacter pylori has become recognized as a fundamental pathogen in the development of gastritis and peptic ulcer disease. Bismuth compounds in combination with antibiotics are widely used to treat H. pylori associated peptic ulcer disease. METHODS: In this study we measured and analysed the inhibitory effect of ranitidine bismuth citrate (RBC, Pylorid, Tritec) on the activity and kinetics of phospholipase A2 (PLA2) (E.C.3.1.1.4) of commercial cobra (Naja naja) venom and H. pylori (French press lysates) using L-alpha-dipalmitoyl-(2[1-14C]palmitoyl)-phosphatidylcholine as substrate. RESULTS: Our data suggest that RBC might exert a dose-dependent uncompetitive inhibition on PLA2 activity of both H. pylori and Naja naja venom. the inhibitory effect of RBC on the PLA2 activity cannot be abolished by the optimal concentration of calcium (10 mM), indicating its mechanism to be unrelated to the displacement of calcium from the activation site of the enzyme. CONCLUSION: Our results suggest that one of the mechanisms by which bismuth compounds are therapeutically effective in the treatment of H. pylori associated gastritis is by inhibiting the activity of the degradative PLA2 enzyme secreted by H. pylori. As a consequence of the inhibitory action of RBC on PLA2 of the bacteria, the extracellular and/or intracellular phospholipid components of the gastric mucosal barrier are preserved. (+info)
The effect of Helicobacter pylori eradication on gastro-oesophageal reflux.
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BACKGROUND: Increased prevalence of oesophagitis has been reported following eradication of Helicobacter pylori. We hypothesized that H. pylori eradication might increase gastro-oesophageal acid reflux in patients with reflux oesophagitis. METHODS: Twenty-five consecutive patients (13 male, 12 female) with H. pylori infection and reflux oesophagitis grade I (22 patients) or II (three patients) were enrolled; mean age 49.9 (range 33-75) years. Twenty-four hour intra-oesophageal pH recording was performed before and 12 weeks after eradication of H. pylori, which was achieved using bismuth subnitrate suspension 150 mg q.d.s., oxytetracycline 500 mg q.d.s. and metronidazole 400 mg t.d.s. for 10 days. Eradication was confirmed by 14C-urea breath test 12 weeks after completion of treatment. The patients did not receive acid-suppressive medication. RESULTS: All patients had abnormal gastro-oesophageal reflux before anti-H. pylori treatment. After treatment, there was no significant change in the percentage of total time oesophageal pH < 4 (P=0.46) in the 23 patients in whom the infection had been cured. Nine of the cured patients had increased acid exposure, whereas 14 had decreased acid exposure. No significant change in reflux symptom scores was found. There was no relationship between change in acid exposure and symptom improvement. CONCLUSIONS: Twelve weeks after H. pylori eradication there was no consistent change in gastro-oesophageal acid reflux in patients with mild or moderate reflux oesophagitis. (+info)