Common adverse events associated with an SSRI: meta-analysis of early paroxetine data.

PURPOSE: We wanted to determine to what extent adverse drug effects associated with a selective serotonin reuptake inhibitor (SSRI) were known but not assessed before application for registration of paroxetine. METHODS: With a special permit from the Norwegian Ministry of Health, we obtained reports from 82 clinical trials presented by the paroxetine license holder in 1989. There were 17 double blind, placebo controlled clinical trials with parallel design with 903 patients on paroxetine and 592 on placebo. Altogether 32 adverse effects showed a risk difference (RD) between paroxetine and control groups of more than 0.5%. We did a meta-analysis for each of these adverse effects. We then compared the outcome with the frequencies stated in the Summary of Product Characteristics (SPC) at the time of registration and those reported in the current SPC. RESULTS: At the time of registration 19 of the adverse effects were statistically significant. Only eight of these adverse effects were listed as being common in the first SPC from 1989. Five out of the nineteen adverse effects are not mentioned in the current SPC. Among them are headache with RD 5.4%, decreased libido RD 2.6%, nervousness RD 2.0% and paresthesia RD 1.7%. CONCLUSIONS: Frequently occurring adverse reactions that are included in today's SPC for paroxetine were evident and documented already in the early studies accompanying the application for marketing authorization in 1989. Some other adverse effects observed then are still not mentioned in the SPC of today. Meta-analyses of adverse effects should be mandatory at the stage of first registration of a drug.

HLA-A3 restricted mutant ras specific cytotoxic T-lymphocytes induced by vaccination with T-helper epitopes.

Cytotoxic T-lymphocytes are one of the most important elements of the antitumor defense. Stimulation of cytotoxic T-lymphocytes outgrowth after immunization with mutant ras peptides is a desired goal since these cells may kill tumor cells in vivo. In this study we tested responding peripheral mononuclear cells from a patient with pancreatic adenocarcinoma who had received intradermal peptide vaccination with a mixture of 17-mer mutant ras peptides and granulocyte-macrophage colony-stimulating factor as an adjuvant. Responding peripheral T-cells were cloned by limiting dilution and several CD8(+) cytotoxic T-lymphocytes, specific for the K- RAS 12-Cys mutation were obtained. By using a panel of nonamer peptides containing the 12-Cys mutation and covering position 4-21 in the ras molecule, the 9-mer peptide which was actually recognized by the cytotoxic T-lymphocytes could be identified. HLA-A*0302 could be identified as the antigen-presenting molecule, and the amino acid sequence of the T-cell epitope carries the previously identified HLA-A*0302 binding motif. The nonamer peptide was contained within the vaccine peptide originally used for intradermal immunization of the patient. The cytotoxic T-lymphocytes were capable of killing target cells expressing HLA-A*0302 that coexpressed the K- RAS 12-Cys mutation after transfection. These data demonstrate that the peptide used for vaccination (17-mer) is processed and presented in vivo, and that generation of cytotoxic T-lymphocytes by vaccination with T-helper epitopes may be important for further development of specific immunotherapy of cancer patients.