Pharmacovigilance in the pharmaceutical industry.
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Biomedical subjects
Publications and source records attributed to B S Nilsson.
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Four methods used for obtaining information from patients on adverse drug reactions are reviewed on the basis of personal experience. In the development of new therapeutic drugs the method which records all events experienced by a patient during drug treatment is to be preferred as it increases the possibility of detecting unanticipated or previously unreported adverse reactions. Disadvantage of this method is that a high number of events not related to drug treatment may be recorded, causing problems in analysis of the data.
Fragments of human fibrinogen were tested for ability to suppress activation of human blood lymphocytes by the lectin phytohaemagglutinin (PHA). Measurement of cellular 14C-thymidine uptake was used as an indicator of DNA synthesis and cell proliferation. The tested fragments were obtained by plasmin digestion or by CNBr fragmentation of fibrinogen. Inhibition of uptake, with good dose response relationship, was demonstrated for the plasmic fragment PL-3 and for the CNBr fragment Hol-DSK. Digests of the latter with trypsin and plasmin gave the same effects as the intact fragment. However, reproducibility was poor with PL-3. Hol-DSK gave better reproducibility, but with pronounced interbatch variations. Other fragments of fibrinogen were tested, but gave no effect in the studied concentrations. The reason for the poor reproducibility is discussed.
The results of clinical trials have shown that the general level of side-effects is substantially lower with zimeldine than with tricyclic antidepressants. Data from ordinary clinical usage in Sweden and the U.K. (as opposed to clinical research experience) shows a similar picture. Hypersensitivity reactions, characterized by fever, myalgia and/or arthralgia, and transient increases in transaminases, occur in approximately 1.5% of patients. In rare cases potentially serious neuropathies have been reported.
The immunomodulating ability of fibrinogen fragment (Hol-DSK) and proteolytic enzyme with fibrinolytic activity from Aspergillus oryzae was analysed in CBA/Ca, C57Bl, C3H/HeJ and NMRI mice. Suppressive effects on the blastogenic response to mitogens were noted. No consistent suppressive effect, but sometimes an enhancing one, was recorded on the antibody responses to protein antigens. Administration of Hol-DSK or proteolytic enzyme shortly after the immunization resulted in a slight inhibition of the development of delayed hypersensitivity to picryl chloride in C57Bl but not in CBA mice. When similar administration was done simultaneously with administration of the challenging antigen of picryl chloride or sheep red blood cells in immunized mice, significant impairment of the delayed-type hypersensitivity reaction was noted. The modulating effects by Hol-DSK did not alter the in vitro bacteriocidal effects of peritoneal exudate cells from mice on Escherichia coli.
The use of placebo in controlled clinical trials is a very difficult matter from an ethical point of view. Scientifically it offers probably the best way of obtaining fast and valid conclusions, thus promoting medical progress for the benefit of future patients. On the other hand, some patients may stand the risk of obtaining a suboptimal therapy in a placebo-controlled trial. In general, this latter aspect must be given precedence. Therefore the use of placebo control should be minimized and other control methods encouraged. However, in certain well-defined instances the use of a placebo control can be justified, provided the ethical implications can be handled.
Guinea pigs immunized with intracutaneous BCG more than 10 weeks previously responded with pleurisy to a large dose (2 mg) of BCG injected into the right pleural cavity. The pleurisy was characterized by an initial stage in which the effusion contained predominantly granulocytes. From day 3 to day 17 after induction, lymphocytes were the dominant white cells. From the day 11 onwards there was decrease of fluid volumes and cell numbers, with concomitant induration and subsequent necrosis of regional lymph nodes, swelling of the pleural wall and formation of adhesions. Fluid volumes of 4-15 ml and total lymphocyte yields of, in general, 10-100 million during days 3-11 after induction of pleurisy, make the model suitable for chemical analyses and immunologic studies.
In order to study any correlation between functional properties of lymphocytes in BCG-induced pleural exudation and the development of the pleurisy a previously described experimental model was used. This model with a duration of effusion of more than 17 days has characteristic stages. From the third day and onwards there are lymphocytes in sufficient amount for in vitro cultures. Proliferation of lymphocytes from the fluid was measured as uptake of 14C-thymidine. The response of the lymphocytes to PPD tuberculin and to phytohemagglutinin (PHA) was studied, and their spontaneous activity was measured. Comparisons were made with lymphocytes from regional lymph nodes. Pleural lymphocytes sampled on the third post-induction day did not respond to PPD or PHA stimulation. In later stages, pleural lymphocytes were stimulated by PPD to approximately the same degree as the lymph node lymphocytes. The response to PHA was weak at all stages of pleurisy, though in later stages there were some cases with high values. Variations in activation ability, related to disease staging, were demonstrated. However, low activities, and variability of the responses, without concomitant variations in disease, speak against a connection between the course of disease and functional status of the lymphocytes as measured in this study.
Dipyridamole has been shown to induce proliferative activity in heart muscle capillary wall cells in the rat. To test whether this effect is due to direct cellular stimulation we tested the substance in various in vitro systems (human lymphocytes, glial cells and endothelial cells; and bovine endothelial cells). During these conditions dipyridamole did not influence cellular proliferation. In all cell systems tested, uptake of labelled thymidine showed an inhibition by dipyridamole. This confirms the earlier finding that dipyridamole inhibits nucleoside uptake, and extends the finding to human cells.
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Nineteen seriously ill patients with suspected or verified tuberculosis were treated with a new formulation of rifampicin for intravenous use. The normal dosage was 300 mg twice a day. Local reactions at the injection site were noted in four patients but no serious adverse reactions were observed. The serum concentrations were similar to those after the same dose given orally.
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A young man had a mild, slightly progressive pulmonary sarcoidosis. After 4 years he developed an acute disease with splenomegaly, anemia, marked elevation of ESR, hypercalcemia and mild renal insufficiency. The anemia and ESR elevation disappeared after splenectomy, whereas the hypercalcemia still needs corticosteroid treatment. Attempts to withdraw this treatment resulted in recurrence of the hypercalcemia, but no other abnormalities. In contrast to other organs examined, the sarcoid tissue in the spleen revealed necrosis formation, consistent with a recent process. A Kveim antigen preparation from the spleen was less potent than antigen from mediastinal lymph nodes. It is suggested that the acute phase of the disease involved mainly the spleen. Speculations about the possible role of infectious agent(s) are put forward.