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AIM: To assess the efficacy, safety and tolerability of different doses of tofogliflozin, a novel, highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS: In a 12-week, multicentre, multinational, randomized, double-blind, parallel-group, placebo-controlled, dose-finding study, patients with inadequate glycaemic control from diet and exercise alone, or from diet and exercise plus a stable dose of metformin, were randomized to one of five doses of tofogliflozin (2.5, 5, 10, 20, or 40 mg) or placebo. The primary efficacy endpoint was absolute change at week 12 from baseline in glycated haemoglobin (HbA1c), minus the change in the placebo group. RESULTS: Statistically significant dose-dependent reductions in HbA1c were shown in all treated groups except the 2.5-mg dose group, with a maximum reduction of 0.56% (placebo-subtracted) at the 40-mg dose, along with increased urinary glucose excretion. Metformin treatment had no substantial influence on tofogliflozin efficacy. Dose-dependent reductions in fasting plasma glucose and body weight were observed, and glucose intolerance was improved, with a trend towards blood pressure reduction. Slight increases were observed for mean ketone bodies with no abnormal change in ketone body ratio. No deaths or treatment-related serious adverse events were reported. The incidence of adverse events was similar in the placebo (37.9%) to that in the tofogliflozin group (35.9-46.3%). Withdrawal because of adverse events was rare (≤2 patients per treatment group), with similar rates of withdrawal in the placebo and tofogliflozin groups. CONCLUSIONS: A once-daily dose of tofogliflozin for 12 weeks was an effective, safe and well-tolerated treatment for T2DM.

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The risk of presenting adverse drug reactions (ADR) is greater for elderly patients. Chronological age is not an independent risk factor for ADRs, but age-dependent factors such as polymedication, multiple diseases and changes in pharmacokinetics and pharmacodynamics seem to be responsible for the risk of developing more adverse drug reactions. We analyzed the ADRs spontaneously reported to the Swiss Drug Monitoring Centre (SANZ) between 1981 and 1995. Age-specific relative incidences of the reported ADRs affecting different organ systems were calculated. For elderly patients we found a decrease in the relative incidence of dermatological ADRs and an increase in neuropsychic and hematological ADRs. The incidence of serious ADRs increased by 8.7% in older patients (> 70 years). The results of this analysis of spontaneous reports were inconsistent with results from epidemiological studies. The possibility and reasons for under-reporting ADRs occurring in elderly patients are discussed.

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20-25% of antibiotics-associated diarrhea cases are caused by infection with toxin-producing Clostridium difficile. Since the advent of broad-spectrum antibiotics Clostridium difficile-associated diarrhea has been observed both in ambulatory practice and as a nosocomial infection in medical and nursing institutions. Clindamycin, aminopenicillins, and cephalosporines are by far the most common triggers for this infection. We reviewed all cases of Clostridium difficile-associated diarrhea due to cephalosporines which were reported to the Swiss Drug Monitoring Center (SANZ) between 1981 and 1995. 87 cases were reported (0.9% of 9720 spontaneous reports in this period), 69 (79%) of which were considered to be due to cephalosporines. In 74% of the cases the indication for the antibiotic treatment was an upper respiratory tract infection. 61 patients received cephalosporines by oral route and 9 patients by intravenous route. Two patients had to be hospitalized. There were no deaths. The pathogenesis, clinical picture, and therapy of Clostridium difficile-associated diarrhea is discussed. We conclude from these cases in the spontaneous reporting system of SANZ that Clostridium difficile infection due to cephalosporines is a frequent occurrence. Because the course can be severe, cephalosporines should be used restrictively.

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One of the most important objects of post-marketing surveillance is the early detection of serious, unknown and unexpected adverse events. As spontaneous reported adverse events vary considerably in their signal-generating value the Swiss Drug Monitoring Center SANZ implemented an early signal detection system in 1991. With a set of screening criteria the individual case reports are automatically checked by the system and read into a signal file. Subsequently these potential signals are processed to quantify the signal generating value of the particular case. According to the screening criteria 2072 (53%) of the reported cases were considered as potential signals. After validating and quantifying their signal value 27% (565) were drug-related and unlabelled, 8% (173) were also rated as serious. On the basis of these cases 114 labelling changes were made. Some of the most interesting cases are discussed. This computer-assisted early signal generation model in a small country with 7 million inhabitants has a high detectability of new, rare, serious and quality of life affecting adverse drug reactions (ADRs). These newly detected ADRs must be interpreted in cognizance of the limitations and restrictions of spontaneous reporting and do not allow pharmacoepidemiologic conclusions.

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Drug-induced liver diseases are potentially avoidable. Hepatotoxic drugs can mimic virtually any form of liver disease. Among all voluntary adverse drug reaction reports to central registries, 4-7% refer to drug-induced liver diseases. We analyze all cases of coumarin-induced hepatic injuries reported on a voluntary basis to the Swiss Drug Monitoring Centre (SANZ) and the Pharmacovigilance Centre (IKS) from 1981 to 1995. During this period the SANZ collected 9720 reports, 674 of which (6.9%) referred to the liver and the biliary tract. In only 11 reports an oral anticoagulant was involved. In 8 cases we assumed at least a possible causal relationship. 2 more cases were reported directly to the IKS. Among these 10 cases 7 were related to phenprocoumon and 3 to acenocoumarol. In 4 cases elevated concentrations of liver enzymes were measured 2-7 days after the beginning of therapy. In the remaining 6 cases the clinical picture was so severe that the patients had to be hospitalized. These 10 cases are discussed and compared with the cases published in the literature. According to our data, hepatic disorders induced by coumarin-anti-coagulants are rare. If hepatitis is diagnosed in a patient treated with oral anticoagulants, the differential diagnosis of a coumarin-induced hepatic injury has to be considered. Crossreactions between the coumarin derivatives phenprocoumon and acenocoumarol are possible.

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Inhibition of gastric acid secretion by drugs remains the most important rational approach to the treatment of acid related diseases. Histamine H2-antagonists and more recently the proton pump blockers have become the first line treatment for acid peptic diseases. Proton pump blockers bind specifically to the proton pump of the parietal cells and thus inhibit the final acid secretion independently from the activating stimuli. Because of this specific mechanism fewer adverse effects on other systems in the body are expected with proton pump blockers than with histamine antagonists. An analysis of the spontaneous reports which the Swiss Drug Monitoring Center (SANZ) received from 1981 to 1995 showed striking differences in the adverse drug reaction profile: hypersensitivity reactions with fever and anaphylactic reactions, liver disorders such as cholestatic hepatitis, most with severe progression and requiring hospitalization, as well as endocrine disorders were reported more frequently with histamine antagonists, skin reactions and joint disorders, however, were reported more often with proton pump blockers. Our data also support the conclusion that adverse drug reactions to proton pump blockers and histamine antagonists are rare in the spontaneous reporting scheme (reporting rate < 1%). There was a somewhat higher rate of serious reports with histamine antagonists. These data do not allow conclusions concerning long-term effects or effects with larger than recommended dosages.

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