Is eradication of Helicobacter pylori with colloidal bismuth subcitrate quadruple therapy safe?

BACKGROUND: When standard triple therapy fails to eradicate Helicobacter pylori, quadruple 'rescue' therapy is often used which, in Europe, generally comprises colloidal bismuth subcitrate (CBS) based triple therapy and a proton pump inhibitor. Since hypochlorhydria could greatly increase absorption of the toxic bismuth ion from CBS, we investigated the bismuth status of patients receiving anti-H. pylori quadruple therapy. MATERIALS AND METHODS: In a prospective open label study 34 patients with nonulcer dyspepsia or peptic ulcer disease, who had failed to eradicate H. pylori with standard triple therapy, were subsequently treated with CBS, omeprazole, amoxycillin and metronidazole (BOAM). A further 35 patients received triple therapy for the eradication of H. pylori: CBS, amoxycillin and metronidazole (BAM) (n = 18); placebo bismuth, amoxycillin and metronidazole (AM) (n = 9); or omeprazole, amoxycillin and metronidazole (OAM) (n = 8). Whole blood bismuth levels were determined before and within 24 hours of completing treatment. Analysis of bismuth was by inductively coupled plasma mass spectrometry, and concentrations were compared between groups and with the Hillemand 'alarm level' for blood bismuth (50-100 microg/l). RESULTS: BOAM gave higher blood bismuth levels than BAM (difference in means 13.1, CI 6.0-20.2, p <.001); three (8.8%) patients taking BOAM had concentrations within the Hillemand alarm level at 54.2, 64.7 and 91.8 microg/l. OAM and AM did not alter baseline blood bismuth levels. CONCLUSIONS: Caution should be observed in prescribing CBS with gastric acid suppression, and alternative bismuth preparations should be considered.

Double-blind comparison of absorbable colloidal bismuth subcitrate and nonabsorbable bismuth subnitrate in the eradication of Helicobacter pylori and the relief of nonulcer dyspepsia.

BACKGROUND: Bismuth is widely used for the eradication of H. pylori, especially in developing countries, although there are concerns over its neurotoxicity. Whether bismuth has to be absorbed in humans to act against H. pylori is not known. In this study, we compared "absorbable" (colloidal bismuth subcitrate) and "nonabsorbable" (bismuth subnitrate) bismuth as part of triple therapy in the eradication of H. pylori. MATERIALS AND METHODS: A double-blind, randomized, placebo-controlled trial was carried out with 120 H. pylori-positive patients with nonulcer dyspepsia. Group CBS + Ab (n = 35) received colloidal bismuth subcitrate (one tablet qds), amoxicillin (500 mg qds), and metronidazole (400 mg tds). Group BSN + Ab (n = 35) received bismuth subnitrate (two tablets tds) and the same antibiotics. Group Ab (n = 35) received placebo bismuth (two tablets tds) and the antibiotics. Group BSN (n = 15) received bismuth subnitrate (two tablets tds) and placebo antibiotics. Bismuth was taken for 4 weeks and the antibiotics for the first 2 weeks. H. pylori eradication, side effects, compliance, pre- and post-treatment symptom scores, and bismuth absorption were assessed. RESULTS: H. pylori eradication was 69%, 83%, 31%, and 0% in CBS + Ab, BSN + Ab, Ab, and BSN, respectively. Side effects, compliance, and symptom relief were similar in all groups, but blood bismuth levels were significantly greater in CBS + Ab than the other three groups. CONCLUSION: The efficacy of bismuth-based therapies as part of triple therapy in the eradication of H. pylori is unrelated to absorption. Hence, the use of effective but poorly absorbed bismuth preparations should be encouraged for bismuth-based eradication therapies.

Solubility, absorption, and anti-Helicobacter pylori activity of bismuth subnitrate and colloidal bismuth subcitrate: In vitro data Do not predict In vivo efficacy.

OBJECTIVES: The aim of this study was to compare the dissolution, bioavailability, and anti-Helicobacter pylori activity of bismuth subnitrate and colloidal bismuth subcitrate. This could, first, provide insights into the mechanism of action of bismuth and, second, help to develop optimal therapeutic strategies. METHODS: Solubility and aquated size of bismuth species were determined in human gastric juice, while absorption into blood and urinary excretion of bismuth was determined in volunteers. Activity against H. pylori was determined in vitro in the presence and absence of antibiotics, while H. pylori eradication was compared in vivo. RESULTS: Bismuth from colloidal bismuth subcitrate was at least 10% soluble and ultrafilterable and was absorbed in volunteers (>0.5%), whereas that from bismuth subnitrate was insoluble and not absorbed (<0.01%). Colloidal bismuth subcitrate was active against H. pylori (mean inhibitory concentration, 400 microg/ml); neither was synergistic with antibiotics. With in vivo triple therapy, bismuth subnitrate was as effective as colloidal bismuth subcitrate in eradicating H. pylori (74% and 70% eradicated, respectively). CONCLUSIONS: Colloidal bismuth subcitrate, unlike bismuth subnitrate, is partially soluble, absorbed in humans, and directly toxic to H. pylori in vitro. Surprisingly, however, these preparations had similar efficacy in vivo against H. pylori within triple therapy, suggesting that bismuth compounds may also exhibit indirect antimicrobial effects. We propose that this is an effect on the gastric mucus layer. Nonabsorbable bismuth compounds should be preferentially considered in bismuth-based therapies against H. pylori, as they would minimize toxicity while maintaining efficacy.

Sclerosing mesenteritis involving the pancreas: two cases of a rare cause of abdominal mass mimicking malignancy.

Two patients presented with abdominal pain and weight loss and each was found to have an abdominal mass involving the pancreas and small bowel mesentery. In both cases a malignant process was suspected clinically, radiologically and surgically. Multiple biopsy specimens in both patients showed dense fibrosis, chronic inflammation and fat necrosis with pancreatic infiltration. Histological opinions included the differential diagnosis of retroperitoneal fibrosis but, with the knowledge of the presence of localized masses, these cases were eventually considered to be due to sclerosing mesenteritis. Direct involvement of the pancreas has not previously been highlighted and led to diagnostic difficulty. Both patients have responded to treatment with corticosteroids. Interestingly, one of the patients subsequently developed a tubulo-interstitial nephritis, which has not previously been reported as associated with sclerosing mesenteritis. This has also responded to corticosteroid treatment.

Treatment outcome in presumed and confirmed AIDS-related primary cerebral lymphoma.

A retrospective analysis identified 38 HIV seropositive patients with a diagnosis of presumed (n = 26) or confirmed (n = 12) primary cerebral lymphoma (PCNSL). All patients had failed to respond to empirical antitoxoplasma therapy and the clinical diagnosis of PCNSL was confirmed by brain biopsy (n = 4), cerebrospinal fluid (CSF) examination for Epstein-Barr virus (EBV) by PCR (n = 7) or postmortem examination (n = 1). There was no difference in the age, performance status, CD4 counts, antiretroviral usage or interval since first HIV serodiagnosis between patients with presumed or confirmed PCNSL. 16 patients received either radiotherapy (n = 14) or chemotherapy (n = 2). Patients with confirmed or presumptive PCNSL were equally likely to receive treatment. The median overall survival, which was measured from the end of unsuccessful antitoxoplasma therapy, was 1.2 months for the whole cohort. There was no difference in overall survival between patients with presumptive (median 0.8 months) and confirmed (median 1.3 months) PCNSL (logrank P = 0.69). This suggests that there may be little value in positively diagnosing PCNSL in the current diagnostic algorithm. Recent improvements in outcome have been reported with systemic chemotherapy in HIV-PCNSL and may influence the need for earlier definitive diagnosis in the future.

Bronchopulmonary Kaposi's sarcoma in 106 HIV-1 infected patients.

The objectives of this study were to describe the clinical and radiological features at presentation, and the natural history of HIV-related bronchopulmonary Kaposi's sarcoma. A retrospective review of medical records and chest radiographs was performed in 106 HIV-infected homosexual men with bronchopulmonary Kaposi's sarcoma diagnosed at bronchoscopy between September 1988 and November 1994. The majority of patients had evidence of advanced HIV disease at diagnosis (median CD4 cell count was 15 x 10(6)/l, range 0-288), and 93% had had a diagnosis of cutaneous Kaposi's sarcoma for a median duration of 11 months prior to diagnosis of their bronchopulmonary disease. The most frequent symptoms at presentation were cough (92%), dyspnoea (69%), pleuritic pain (20%), haemoptysis (13%) and wheezing (10%). The most common radiological finding in 73% of our series was of poorly defined and confluent opacities, with predominant middle and lower zone involvement. Median survival was 4 months (range 0-37 months) from diagnosis and 9 months (range 1-25) from the onset of symptoms. Treatment with either chemotherapy or radiotherapy was associated with a significantly reduced risk of death (hazards ratio (HR)=0.48, 95% CI=0.26-0.87). Factors associated with a poor survival, after adjustment for treatment effect were older age (HR=1.79, 95% CI=1.22-2.84) for each 10-year increase in age; a history of pleuritic pain (HR=2.97, 95% CI=1.39-6.32); presence of pleural effusion on X-ray (HR=2.01, 95% CI=1.13-3.59) and a prior diagnosis of cutaneous Kaposi's sarcoma (HR=1.8, 95% CI=1.00, 3.24). Bronchopulmonary Kaposi's sarcoma occurs mainly in patients with advanced HIV disease and a prior history of cutaneous disease. Survival is poor, and adverse prognostic factors include older age at diagnosis and the presence of pleural disease.

Activity of thalidomide in AIDS-related Kaposi's sarcoma and correlation with HHV8 titre.

A phase II study of thalidomide was conducted to evaluate its efficacy and toxicity in the treatment of cutaneous AIDS-related Kaposi's sarcoma (AIDS-KS). To evaluate whether clinical response is correlated with titre of human herpesvirus 8 (HHV8) DNA in peripheral blood, levels were determined by serial end-point dilution at enrolment and 4-6 weeks later. Seventeen male HIV-seropositive patients with histopathologically diagnosed KS were treated with thalidomide 100mg orally once nightly for 8 weeks. Response evaluation was performed using AIDS Clinical Trials Group (ACTG) criteria and analysis was by intention to treat. Six of 17 patients achieved a partial response (35%: 95% confidence interval 10-61%). Eight patients withdrew (6 owing to toxicity, one to early progression and one to non-compliance). HHV8 DNA load decreased by at least 3log10 to undetectable levels in 3 of the 5 virologically assessable partial responders. This preliminary study demonstrates that thalidomide has activity in the treatment of AIDS-KS and that clinical response is associated with a reduction of HHV8 DNA titre in peripheral blood.

Phase II trial of 13-cis-retinoic acid for poor risk HIV-associated Kaposi's sarcoma.

Fifteen men with HIV-associated Kaposi's sarcoma (KS) and poor risk disease according to the TIS staging were enrolled in a phase II trial of oral 13-cis-retinoic acid. The median CD4 cell count was 95 cells/microl (range 7-260) and 6 had prior AIDS-defining opportunistic infections. One patient was withdrawn on account of cutaneous toxicity. Evaluation was by AIDS Clinical Trials Group (ACTG)1 defined assessment. One patient achieved a partial response and remains on treatment in partial remission. Thus the overall response rate is 7% (95% confidence interval 0-23%). A further 5 patients had stable disease (38%: 95% confidence interval 7-64%). The overall low activity, considerable toxicity and limited cosmetic benefit even in responding patients limits the value of this approach in KS. However, this treatment strategy may be more rewarding in early good risk KS.

Epidermoid anal cancer in HIV infected patients.

Anal cancer associated with human immunodeficiency virus (HIV) infection is an unusual clinical situation in which the appropriate management remains unclear. Experience of treatment and follow-up is presented of six patients with histologically confirmed invasive epidermoid anal cancer on a background of HIV infection. Durable complete responses with acceptable toxicity occurred in two patients with moderate immunosuppression and Stage I-II tumours treated with a combination of concomitant chemotherapy (5-fluorouracil and mitomycin-C) and pelvic radiotherapy (45 Gy in 25 fractions). One patient treated with radiotherapy alone (60 Gy in 30 fractions in two phases) had a complete response. Two patients, one with Stage III tumour and the other with pre-existing acquired immunodeficiency syndrome, died within 6 months of treatment. Moderate to severe perianal skin reactions commonly occurred. Although the world experience of managing anal cancer in HIV infected individuals is small, this and other reports support the use of chemoradiotherapy in selected patients. The appropriate treatment of patients with more advanced tumours and/or advanced HIV infection is uncertain.

The infra-red coagulator in the treatment of AIDS-related Kaposi's sarcoma and a comparison with radiotherapy.

Experience with 1 s pulses of the infra-red coagulator is reported for the treatment of 10 cutaneous AIDS-related Kaposi's sarcoma lesions in seven patients. The infra-red coagulator may be a useful addition in the palliative cosmetic treatment of Kaposi's sarcoma, producing an acceptable result in small (less than 2 cm in diameter) Kaposi's sarcoma lesions of the arms and trunk, but not in those situated on the legs.

High dose dexamethasone and base of brain irradiation for hormone refractory metastatic carcinoma of the prostate.

High dose dexamethasone combined with irradiation to the base of the brain achieved a dramatic beneficial effect in two terminal cases of widespread metastatic carcinoma of the prostate involving cranial nerves and the entire skeleton. Pain requiring very large doses of analgesics and anemia requiring blood transfusions every 3-4 weeks were improved rapidly. No further transfusions were needed.

Excision of a clival and upper cervical pheochromocytoma by an extended maxillotomy approach: a case report.

By use of an extended maxillotomy approach, greater surgical access is provided to the midline skull base in comparison with lateral approaches. We describe this technique used to debulk a tumor extending from the sphenoid sinus across the craniocervical junction to the second cervical vertebrae.

Liposomal daunorubicin in advanced Kaposi's sarcoma: a phase II study.

We report a non-randomized Phase II clinical trial to assess the efficacy and safety of liposomal daunorubicin (DaunoXome) in the treatment of AIDS related Kaposi's sarcoma. Eleven homosexual men with advanced Kaposi's sarcoma were entered in the trial. Changes in size, colour and associated oedema of selected 'target' lesions were measured. Clinical, biochemical and haematological toxicities were assessed. Ten subjects were evaluated. A partial response was achieved in four, of whom two subsequently relapsed. Stabilization of Kaposi's sarcoma occurred in the remaining six, maintained until the end of the trial period in four. The drug was generally well tolerated, with few mild symptoms of toxicity. The main problem encountered was haematological toxicity, with three subjects experiencing severe neutropenia (neutrophil count < 0.5 x 10(9)/l). There was no evidence of cardiotoxicity. In this small patient sample, liposomal daunorubicin was an effective and well tolerated agent in the treatment of Kaposi's sarcoma.

Responses of liver metastases to radiotherapy and razoxane.

Twenty-five patients with liver metastases, chiefly due to colorectal cancer, were given a loading dose of razoxane for 3 days before 5 consecutive days of radiotherapy to the whole liver. Patients also took razoxane during the radiotherapy and then for one month afterwards. Liver tumour volume was measured on CT scans using the ELSCINT 3D soft tissue imaging programme just before and 4 weeks after the end of radiotherapy treatment. Twelve of the 25 patients had tumour volume reductions of more than 50%. The overall major response rate therefore is 12/25 (48%). In two of the major responders the liver metastases were due to recurrent stomach cancer. In addition to the 12 responders, four patients had a reduction of more than 20% but less than 50%, thus giving an overall response rate of 16/25 (64%). These results can form the basis of a formal, randomized, controlled clinical trial of radiotherapy alone (or any other treatment) compared with radiotherapy and razoxane in the difficult and life threatening condition presented by liver metastases.