Retinopathy associated with high-dose interferon alfa-2b therapy.

PURPOSE: To present seven patients who developed retinopathy while receiving high-dose interferon alfa-2b therapy for adjuvant treatment of high-risk melanoma. METHODS: Retrospective case series. RESULTS: Seven patients developed a retinopathy while receiving high-dose interferon alfa-2b therapy for adjuvant treatment of high-risk melanoma. Five patients had normal visual acuity, but retinopathy with cotton- wool spots and/or retinal hemorrhages with the retinopathy resolved after stopping treatment after detection. Two patients developed severe retinopathy with vision loss to counting fingers and hand motions without resolution of the retinopathy. The duration of the maintenance treatment before detection of the retinopathy for all patients ranged from 6 to 26 weeks. The total dose received at time of detection of retinopathy ranged from 816 to 1770 million units. Confounding factors included hypertension, thrombocytopenia, anemia, and a history of prior chemotherapy in one patient. Also, one patient received an investigational ganglioside vaccine, one had a history of radiation treatment to the brain, and six received paroxetine. CONCLUSIONS: Patients receiving interferon alfa-2b are at risk for developing an associated retinopathy. The risk appears to be greater with higher dosage therapy. In addition, severe vision loss can be seen with interferon alfa-2b-associated retinopathy. The effect of treatment with selective serotonin reuptake inhibitors, such as paroxetine, in increasing the incidence of this complication is unknown. Patients need to be monitored until the retinopathy is resolved to screen for sequelae, including retinal neovascularization.

High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696.

PURPOSE: High-dose interferon alfa-2b (IFNalpha2b) is the only established adjuvant therapy of resectable high-risk melanoma. GM2-KLH/QS-21 (GMK) is a chemically defined vaccine that is one of the best developed of a range of vaccine candidates for melanoma. A single-institution phase III trial conducted at Memorial Hospital served as the impetus for an intergroup adjuvant E1694/S9512/C509801 trial, which recently completed enrollment of 880 patients. To build on the apparent benefit of IFNalpha2b in resectable high-risk American Joint Committee on Cancer (AJCC) stage IIB or III melanoma, this phase II study was designed to evaluate the combination of GMK and IFNalpha2b. The E2696 trial was undertaken to evaluate the toxicity and other effects of the established adjuvant high-dose IFNalpha2b regimen in relation to immune responses to GMK and to evaluate the potential clinical and immunologic effects of the combined therapies. PATIENTS AND METHODS: This trial enrolled 107 patients with resectable high- or very high-risk melanoma (AJCC stages IIB, III, and IV). RESULTS: The results demonstrate that IFNalpha2b does not significantly inhibit immunoglobulin M or G serologic responses to the vaccine and that the combination of high-dose IFNalpha2b and GMK is well tolerated in this patient population. CONCLUSION: Cox analysis of the results of the combination with IFNalpha2b show improvement in the relapse-free survival of patients with very high-risk melanoma (including those with resectable M1 disease).

Paroxetine for the prevention of depression induced by high-dose interferon alfa.

BACKGROUND: Depression commonly complicates treatment with the cytokine interferon alfa-2b. Laboratory animals pretreated with antidepressants have less severe depression-like symptoms after the administration of a cytokine. We sought to determine whether a similar strategy would be effective in humans. METHODS: In a double-blind study of 40 patients with malignant melanoma who were eligible for high-dose interferon alfa therapy, we randomly assigned 20 patients to receive the antidepressant paroxetine and 20 to receive placebo. The treatment was begun 2 weeks before the initiation of interferon alfa and continued for the first 12 weeks of interferon alfa therapy. RESULTS: During the first 12 weeks of interferon alfa therapy, symptoms consistent with a diagnosis of major depression developed in 2 of 18 patients in the paroxetine group (11 percent) and 9 of 20 patients in the placebo group (45 percent) (relative risk, 0.24; 95 percent confidence interval, 0.08 to 0.93). Severe depression necessitated the discontinuation of interferon alfa before 12 weeks in 1 of the 20 patients in the paroxetine group (5 percent), as compared with 7 patients in the placebo group (35 percent) (relative risk, 0.14; 95 percent confidence interval, 0.05 to 0.85). The incidence of adverse events was similar in the two groups. CONCLUSIONS: In patients with malignant melanoma, pretreatment with paroxetine appears to be an effective strategy for minimizing depression induced by interferon alfa.

Neoadjuvant interferon alfa-2b treatment in a murine model for metastatic ocular melanoma: a preliminary study.

OBJECTIVES: To investigate the treatment of metastasis from uveal melanoma and to test the effect of interferon (IFN) alfa-2b in a murine model. METHODS: The B16-LS9 tissue culture melanoma cells were inoculated into the posterior intraocular compartment of 3 groups of C57BL/6 mice. The inoculated eyes were enucleated at 9 days and the mice were euthanized at 26 days after inoculation; the site and number of metastases were determined using standard histologic techniques. Group 1 was the control group; group 2 was given 20,000 international units (IU) of IFN alfa-2b intramuscularly 12 hours before enucleation, and group 3 received daily injections of 20,000 IU of IFN alfa-2b intramuscularly starting 4 days before enucleation. RESULTS: Pulmonary metastases were detected in 57%, 33%, and 0% of groups 1, 2, and 3, respectively; hepatic micrometastases were detected only in group 1. These results showed a significant decrease in hepatic metastases in mice receiving IFN alfa-2b vs controls (P =.005). CONCLUSION: Treatment with IFN alfa-2b results in decreased hepatic metastases from intraocular melanoma in a murine model. Arch Ophthalmol. 2000;118:1085-1089

Peptic ulcer bleeding: accessory risk factors and interactions with non-steroidal anti-inflammatory drugs.

AIMS: To determine risk factors for peptic ulcer bleeding other than non-steroidal anti-inflammatory drugs (NSAIDs). Methods-Data on possible antecedent risk factors obtained in a large case control study of 1121 patients admitted to hospitals in Glasgow, Newcastle, Nottingham, Oxford, and Portsmouth with bleeding peptic ulcers were compared with the same information obtained in 989 population controls. Data were analysed by logistic regression with the calculation of odds ratios (OR) and 95% confidence intervals (CI). RESULTS: From a logistic regression model, oral anticoagulants (OR 7. 8; 95% CI 2.8-21.5), previous peptic ulcer (3.8; 2.6-4.9), treatment for heart failure (5.9; 2.3-13.1), oral corticosteroid use (2.7; 1. 3-4.5), treatment for diabetes (3.1; 1.2-4.3), and current smoking (1.6; 1.2-2.0) were all independent risk factors. No association was found with use of calcium channel antagonists. Odds ratios for concomitant NSAID usage were multiplicative with the exception of current smoking. CONCLUSIONS: Some 45% of admissions for peptic ulcer bleeding in England and Wales in those aged 60 or more are calculated to be attributable to, or associated with, these accessory risk factors, which, together with those associated with aspirin or other NSAID use will account for over 80% of predisposing factors to ulcer bleeding.

The General Practice Research Database. Scientific and Ethical Advisory Group.

We describe a powerful new information resource for pharmacovigilance, pharmaco-economic studies, clinical epidemiology and health service research, which involves automated linkage of demographic, diagnostic and prescription information on some 3.4 million patients enrolled in over 500 separate general practices. Information is subject to regular validation checks. Access to this resource is available for bona fide research workers, subject to appropriate safeguards for patient anonymity and for scientific and ethical standards of the proposed studies. This database has depended upon the participating general practitioners and has already resulted in a substantial output of studies in peer-reviewed literature. It has great potential for further work of major relevance to public health, and its increasing use is to be actively encouraged.

Postmarketing surveillance of the safety of cimetidine: 15-year mortality report.

The pattern of mortality after 15 years of observation is reported among almost 10,000 patients who were taking cimetidine when they were first recruited between 1977 and 1980. Many took the drug for a number of years, some switching to other antisecretory agents as the study progressed. The findings are reassuring and provide no evidence of any long-term adverse effects of cimetidine which might be detected by monitoring mortality rates. The data have also been used to examine the possible positive relationships between aluminium ingestion and Alzheimer's disease and H. pylori infection and ischaemic heart disease. No significant evidence was obtained in support of the existence of these relationships.

European postmarketing surveillance of ramipril in hypertension. 1. Feasibility and study cohort.

A prospective observational cohort study of the angiotensin inhibitor, ramipril, was undertaken in four countries within the European Community-Netherlands, United Kingdom, Germany and Belgium. A total of 10,377 consecutive patients with essential hypertension were recruited to the study with the aim of follow-up for one year. Overall 37% of doctors who agreed to participate in the study actually enrolled at least one patient. One third of the doctors who enrolled patients in the study entered two thirds of patients studied. Some 15% of participating males and 27% of females were aged over 70 years. Newly diagnosed hypertensives comprised 22% of the study cohort, the proportion being highest in UK and Netherlands, whereas 53% were established hypertensives of two or more years' duration, the proportion being highest in Germany and Belgium. There were substantial differences among the participating countries in the concurrent treatment these patients were receiving for hypertension, with two or more co-therapies being most frequent in Germany and Belgium. There were also substantial differences in co-therapies for concurrent diseases among the participating countries, reflecting both standard therapeutic practices in local areas and differences in marketing of drugs in the different countries. This report describes the initial findings of this multinational study and emphasises the need to consider several major potentially confounding variables in the analysis of the outcome events both in this study and in other collaborative observational international monitoring schemes for adverse drug reactions.

Conservative treatment of early-stage breast cancer. The Emory experience.

Between January 1983 and December 1991, 80 women with AJCC clinical stage I or II breast cancer were treated with conservative surgery and radiation therapy. Reexcision of the primary was performed in 40 breasts, and residual tumor was identified in 40% of these. Margins of resection were assessed in 80% and, of these, 46 patients had final margins of resection that were negative, 86% had axillary node dissection, 45 patients had histologically negative axillary nodes, and 24 had histologically positive axillary nodes. Of patients with histologically positive lymph nodes, 92% received systemic adjuvant treatment consisting of chemotherapy in 19/24 and tamoxifen in 14/24. Median follow-up was 34 months (range: 6-90 months). The adjusted 5-year actuarial Overall Survival for the group was 92%, and Disease-Free Survival was 80%. The 5-year Local Recurrence-Free Survival was 96%. The present study confirms the excellent results that can be obtained with conservative surgery plus radiation therapy.

Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs.

Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of peptic ulcer complications, but it is not clear whether some drugs are more likely than others to cause such complications. We compared previous use of NSAIDs in 1144 patients aged 60 and older admitted to hospitals in five large cities with peptic ulcer bleeding and in 1126 hospital controls and 989 community controls matched for age and sex. Peptic ulcer bleeding was strongly associated with use of non-aspirin NSAIDs of any type during the 3 months before admission (411 cases, 351 controls; odds ratio 4.5 [95% CI 3.6 to 5.6]). The odds ratios for peptic ulcer bleeding were lowest for ibuprofen (2.0 [1.4-2.8]) and diclofenac (4.2 [2.6-6.8]), and intermediate for indomethacin, naproxen, and piroxicam (11.3 [6.3-20.3], 9.1 [5.5-15.1], and 13.7 [7.1-26.3]). Azapropazone and ketoprofen carried the highest risks (31.5 [10.3-96.9] and 23.7 [7.6-74.2]). Risks also increased with drug dose (low dose 2.5 [1.7-3.8], intermediate 4.5 [3.3-6.0], and high 8.6 [5.8-12.6]) for all drugs combined. Appropriate clinical strategies could prevent many episodes of peptic ulcer bleeding: NSAIDs should be used only in patients who do not respond to other analgesics; the lowest possible doses should be used; and the least toxic NSAIDs should be selected.

Postmarketing surveillance versus clinical trials: which benefits the patient?

Both randomized controlled clinical trials and observational postmarketing surveillance studies have a place in providing information to physicians and patients on effectiveness and safety of new medicines. Prelicensing is the realm of the basic scientist producing a medicine which is available for investigation by clinical trial. In this context, manufacturers attempt to define the efficacy for desired indications and to establish an appropriate dosage for the drug. To do so, they usually confine attention to idealized standard patients, excluding all complex problems, such as pregnancy, renal or other organ failure, comorbidity, the elderly, the child, and so forth. Postmarketing surveillance covers the range of observational studies undertaken after marketing including cohort studies, case-control studies, and spontaneous reports of suspected adverse drug reactions. These observational studies are less rigorous than clinical trials, but have the potential to provide information from a representative sample of 'real-life' patients. Neither postmarketing surveillance studies nor clinical trials are capable of answering questions fully. In future, record linkage techniques may play a greater role by providing information on data linking drug exposures and outcomes in general practice.

Cancer-related urinary proteinase inhibitor, EDC1: a new method for its isolation and evidence for multiple forms.

During the past several years, numerous laboratories have reported isolation and purification of proteinase inhibitors from human urine. Many of these molecules were incompletely characterized and some of them may have been artifacts in part because of harsh procedures used for their isolation. Consequently, there is disagreement and confusion regarding the biochemical characteristics of these inhibitors. We previously reported the isolation of a proteinase inhibitor, EDC1, from the urine of a leukemic patient. This molecule, M(r) 30 kDa, was antigenically related to plasma inter-alpha-trypsin inhibitor (IATI) and inhibited the growth of a virally transformed B cell line. Immunoreactive EDC1 was also the major component of low molecular weight proteinuria observed in cancer patients. We now report a new method for the isolation of EDC1 from urine of patients with adenocarcinomas of colon and lung and melanoma and compare its partial amino acid sequence with that of HI 30, a proteinase inhibitor previously isolated from pooled normal urine by Hochstrasser et al. [Hoppe-Seyler's Z Physiol Chem 357:153-162, 1976]. Our method involves i) a batchwise cation exchange, ii) gel filtration chromatography, iii) anion exchange chromatography on FPLC, and iv) reverse phase C18 chromatography on HPLC. This method is mild and results in an overall yield of 0.4 to 1.2 mg of EDC1/liter urine. On the basis of the partial N-terminal amino acid sequence of its N terminal (38 residues) and middle regions (29 residues), EDC1 appears to be identical with HI30. Surprisingly, during this isolation procedure, another proteinase inhibitor, M(r) 22 kDa, which cross-reacted with antisera to EDC1 and IATI, was also isolated. The 22 kDa molecule was a major component of the IATI related urinary molecules and was identical with the 30 kDa EDC1 in which first the 15 N terminal residues were clipped. The lower M(r) inhibitor was not an artifact formed during storage or isolation procedure because the Western blot analysis of fresh cancer and normal urine revealed the 30 and 22 kDa molecules. Thus, both the 30 kDa EDC1 (or HI30) and its clipped variant, the 22 kDa molecule, are physiologic components of IATI related urinary proteinase inhibitors and excretion of both forms may be increased in patients with advanced cancer.

Postmarketing surveillance of captopril for hypertension.

1. A scheme for augmented spontaneous reporting of adverse drug events using advanced view data systems was developed and applied to study 67,698 consecutive patients prescribed captopril in general practice for the treatment of hypertension. 2. Captopril was an effective hypotensive agent in this population, as only 1.9% of patients were withdrawn because of apparent inefficacy. 3. Adverse effects of captopril resulted in withdrawal of treatment in 8.9% of recipients, and such effects were more frequent in elderly and female recipients. 4. Skin reactions--usually maculopapular rashes--tended to occur early during therapy whereas cough occurred much later and was reported more frequently in non-smokers. 5. Some 1.1% of recipients died during follow-up. There was no evidence of any unusual or unexpected causes of death which might be partially or totally captopril-related in the study cohort. 6. The study confirms the feasibility of large scale postmarketing surveillance studied in general practice and allowed risk benefit assessments to be made on the use of captopril for treating hypertension.

Postmarketing surveillance of the safety of cimetidine: 10 year mortality report.

A total of 9928 cimetidine users were identified from prescriptions in four centres and followed for 10 years. The 'all-cause' mortality ratio fell from 1.9 in year 1 to 1.0 in years 8 to 10. Most of the early excess in mortality was attributable to cimetidine being given in the late stages of many diseases, often to counter adverse gastric effects of other drugs. Specific causes of mortality during years 5-10 of the study, were generally unremarkable. Significant increases in mortality ratios were apparent, however, for oesophageal cancer (years 5-7, 2.3; years 8-10, 1.9); lung cancer (years 5-7, 1.1; years 8-10, 1.7); diseases of the oesophagus, stomach, and duodenum (years 5-7, 3.3; years 8-10, 2.3); and chronic liver disease (years 5-7, 2.4; years 8-10, 3.3). None of these increases in mortality seems to be attributable to an adverse effect of cimetidine use. Data are also presented for mortality from diseases of the nervous system. Eight deaths (of which one was miscoded) were certified as being from motor neurone disease, representing a mortality ratio of 2.6 for years 2-10 of the study which is of borderline statistical significance. This study confirms that cimetidine is safe. Mortality from some diseases increased over the study period, but selection rather than any adverse effect of the drug is likely to be the explanation.

Randomized study of interleukin 2 (IL-2) alone vs IL-2 plus lymphokine-activated killer cells for treatment of melanoma and renal cell cancer.

The purpose of this study was to evaluate the efficacy and safety of a continuous-infusion interleukin 2 (IL-2) regimen for patients with metastatic melanoma and renal cell cancer. To investigate the contribution of adoptively transferred lymphokine-activated killer cells, patients were randomized to receive either IL-2 alone or IL-2 plus lymphokine-activated killer cells. Twenty-three patients with renal cell carcinoma and 20 with melanoma were entered into the protocol. There were no objective responses noted in the 38 assessable patients (20 with renal cell carcinoma, 18 with melanoma). Most patients demonstrated progressive disease following one 31-day cycle of weekly continuous-infusion IL-2. Grade I and II toxic reactions, including fever, rash, anorexia, and weight gain, were common and treated symptomatically. Significant in vivo stimulation of lymphokine-activated killer and natural killer cell activity was noted in most patients. This continuous-infusion IL-2 regimen with or without lymphokine-activated killer cells was ineffective in the treatment of melanoma and renal cell carcinoma.

Post-cimetidine surveillance for up to ten years: incidence of carcinoma of the stomach and oesophagus.

The long-term effects of cimetidine on the occurrence of gastric and oesophageal cancer were assessed in a prospective cohort study of 9928 patients who had been prescribed cimetidine. They were first identified between 1978 and 1980, and cancer registrations and deaths were identified among them over a period of up to 10 years. One hundred and eleven cancers were identified after the start of cimetidine treatment: 71 were adenocarcinomas of the stomach, 27 were carcinomas of the cardia and/or oesophagus (22 adenocarcinomas, five unknown histology) and the remaining 13 tumours were squamous cell cancers of the oesophagus. Only six patients presented with early gastric cancers. Over a period of eight years the ratio of observed to expected (O/E) gastric cancer deaths has fallen from 10.7 (p < 0.001) to 1.2 (NS). The O/E ratio of oesophageal cancer deaths also fell over the first six years of study, from 5.4 (p < 0.01) to 1.4 (NS) but it has risen slightly in years 7 and 8 to 3.7 (p < 0.05). These findings do not suggest that there is an increased risk of developing oesophageal or gastric cancer from cimetidine treatment, and are generally consistent with cimetidine being used inadvertently to treat the early symptoms of gastric and oesophageal cancer. The slight rise in oesophageal cancer deaths in years 7 and 8 was unexpected and will be the subject of further observation.

Detecting adverse drug reactions - a concise updateI. Cohort and case control studies.

Editorial Note:In the three decades which have passed since the need for more thorough studies of the side effects of pharmaceuticals was thrown into sharp profile by the thalidomide disaster, much has changed in the way in which these unwanted effects of drugs are approached and the extent to which they are understood. The three papers which follow in this issue open a series which seeks to provide a concise update of each of the principal methods which underlie the science and art of adverse reaction study. The papers were presented at a closed meeting jointly organized by the European Regional Office of the World Health Organization and the W.H.O. Collaborating Centre for Public Health Research, Kiel, Germany, on 26-29 November 1990, under the Chairmanship of Prof. Fritz Beske. The series will continue in future issues of the Journal.