Objective: To develop and validate an extensive radiographic scoring system for ankylosing spondylitis (AS). Methods: The Stoke Ankylosing Spondylitis Spinal Score (SASSS) was modified by adding a score for the cervical spine and defining squaring. This modified SASSS (mSASSS) is the sum of the lumbar and cervical spine score (range 0-72). 370 lateral views of the lumbar and cervical spine were used for development of the mSASSS, standardisation of observers, and for studying reliability. In a 48 week NSAID study of 57 patients, change over time and construct validity were studied. Results: Interobserver correlations of the lumbar and cervical spine scores were good (r.0.95). The interobserver duplicate error was 0.55 in a range from 0 to 36. The mean change in the cervical and lumbar spine scores between weeks 0 and 48 of all patients was 1.45 (range 0-6.0) and 1.06 (0-5.0), respectively (paired t testing, p,0.001). Change in radiological score was seen in 36/57 (63%) patients (lumbar and cervical spine 11, cervical spine 12, lumbar spine 13 patients). Conclusion: The mSASSS is useful for assessing extensive radiographic damage in AS. It is reliable, detects changes over 48 weeks, and shows a satisfactory face and construct validity.

Adverse drug effects are manifold and heterogenous. Many situations may hamper the signalling (i.e. the detection of early warning signs) of adverse effects and new signals often differ from previous experiences. Signals have qualitative and quantitative aspects. Different categories of adverse effects need different methods for detection. Current pharmacovigilance is predominantly based on spontaneous reporting and is mainly helpful in detecting type B effects (those effects that are often allergic or idiosyncratic reactions, characteristically occurring in only a minority of patients and usually unrelated to dosage and that are serious, unexpected and unpredictable) and unusual type A effects (those effects that are related to the pharmacological effects of the drug and are dosage-related). Examples of other sources of signals are prescription event monitoring, large automated data resources on morbidity and drug use (including record linkage), case-control surveillance and follow-up studies. Type C effects (those effects related to an increased frequency of 'spontaneous' disease) are difficult to study, however, and continue to pose a pharmacoepidemiological challenge. Seven basic considerations can be identified that determine the evidence contained in a signal: quantitative strength of the association, consistency of the data, exposure response relationship, biological plausibility, experimental findings, possible analogies and the nature and quality of the data. A proposal is made for a standard signal management procedure at pharmacovigilance centres, including the following steps: signal delineation, literature search, preliminary inventory of data, collection of additional information, consultation with the World Health Organization Centre for International Drug Monitoring and the relevant drug companies, aggregated data assessment and a report in writing. A better understanding of the conditions and mechanisms involved in the detection of adverse drug effects may further improve strategies for pharmacovigilance.

Pharmacovigilance is more than spontaneous reporting alone, and the evaluation of marketed medicines is more than just pharmacovigilance. The positioning of a drug usually takes place during the years following introduction, when worldwide experience has accumulated. Originally a modest appendix of drug regulation, pharmacovigilance has become a major activity. The provision of the information needed for the evaluation of the benefits and risks of drugs is in the first place a scientific challenge. In addition, there are important ethical, logistical, legal, financial and commercial constraints. Good pharmacovigilance practice needs to be developed to ensure that data are collected and used in the right way and for the right purpose. Pharmacovigilance, and more generally the study of the benefits and risks of drugs, plays a major role in pharmacotherapeutic decision-making, be it individual, regional, national or international. In addition, pharmacovigilance is becoming a scientific discipline in its own right. A variety of changes are taking place in the complex system of drug development, regulation and distribution. Pharmacovigilance should be proactive in monitoring their possible consequences.

Furosemide delivery rate in the nephron has been reported to be one of the major determinants of diuretic response. In a randomized, crossover double-blind study in eight healthy volunteers, we tested this hypothesis by comparing continuous intravenous infusion of furosemide (infusion rate, 4 mg/hr) during 8 hours after administration of an intravenous loading dose of 8 mg (total dose, 40 mg) with an intravenous bolus injection of 40 mg furosemide. During the study days subjects were rehydrated with isovolumetric amounts of fluid. Mean total urinary volume (Vw), sodium (U,,), potassium, and chloride excretion after 8 and 24 hours were significantly greater after treatment with continuous furosemide infusion when compared with bolus injection, whereas total urinary furosemide excretion showed no differences ( V , , bolus versus V , infusion, 5270 versus 6770 mV8 hours; UNa bolus versus UNa infusion, 314 versus 430 mmoV8 hours; bothp < 0.001). These findings strongly support the concept of the furosemide delivery rate into the nephron as a determinant of diuretic efficiency. (CLIN PHARMACOL THER 1992;s 1:440-4).