The plasma concentration of ophthalmic timolol correlates with several haemodynamic effects. As HR decreases, SVRI increases and blood pressure is kept unchanged.

Abstract. Tirkkonen T, Heikkilä P, Huupponen R, Laine K (University of Turku; Turku University Hospital; and StatFinn Ltd; Turku, Finland). Potential CYP2C9-mediated drug-drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide. J Intern Med 2010; 268: 359-366.Objectives. Sulphonylureas are widely used in the treatment of type 2 diabetes mellitus (T2DM). Based on laboratory findings, we determined the clinical significance of potential CYP2C9-mediated drug-drug interactions in hospitalized patients receiving glibenclamide, glimepiride or glipizide, all of which are metabolized by CYP2C9, together with a CYP2C9 inhibitor.Design, setting and subjects. An observational pharmacoepidemiological database study was performed in a university hospital setting with 3884 patients with T2DM.Main outcome measures. Efficacy and safety of sulphonylurea therapy during the potential interaction (sulphonylurea treatment with a CYP2C9 inhibitor) vs. control periods (sulphonylurea treatment without a CYP2C9 inhibitor) were estimated using laboratory parameters.Results. Almost 20% of patients were exposed to a potential drug-drug interaction with a CYP2C9 inhibitor during sulphonylurea treatment. More than 75% of the potential interactions occurred with trimethoprim, metronidazole and fluconazole. When all sulphonylureas were pooled and adjusted for age, gender, ward and sulphonylurea dose, mean and maximum fasting plasma glucose concentrations as well as maximum values of glycosylated haemoglobin were significantly lower during the interaction periods compared with control periods, whereas mean and minimum activities of alanine amino transferase and gamma-glutamyl transferase were higher. The minimum fasting plasma glucose values were more often below the target range in patients with potential interactions. The sulphonylurea dose did not differ significantly between patients who were or were not concomitantly treated with a potentially interacting drug.Conclusions. Concomitant use of a CYP2C9 inhibitor results in exaggerated pharmacodynamic effects of sulphonylureas and increases the risk of hypoglycaemia in T2DM patients receiving glibenclamide, glimepiride or glipizide.

SUMMARYAims: Clopidogrel is a prodrug that needs to be activated to inhibit platelet aggregation. The objective of this study was to evaluate the prevalence and clinical consequences of potential drug-drug interactions of clopidogrel with drugs affecting CYP3A4 activity. Methods: Co-administrations of clopidogrel together with well-established CYP3A4 inhibitors, CYP3A4 inducers, and atorvastatin were investigated in a population-based pharmacoepidemiological study utilizing data from the national healthcare registers and in more detail from a university hospital register in Finland. The main outcome measures were all-cause mortality and mortality and morbidity related to thrombosis or bleeding. Results: In the nationwide analysis, 6.1%, 1.0%, and 20.8% of the clopidogrel-treated patients were exposed to concomitant use of CYP3A4 inhibitors, CYP3A4 inducers, and atorvastatin, respectively. In the survival analysis, the adjusted hazard ratio for overall mortality was 2.29 (P < 0.001) for CYP3A4 inducer users and 0.74 (P = 0.003) for atorvastatin users compared with controls (patients receiving clopidogrel without interacting medication). CYP3A4 inhibitor use seemed to prevent from thrombosis: HR 0.67, P < 0.001. The hospitalizations due to bleedings were rarer in atorvastatin and CYP3A4 inhibitor groups compared with controls. Thrombosis complications leading to hospitalizations were more often seen in the atorvastatin group than in the control group. Conclusions: No uniform untoward effect of concomitant CYP3A4 inhibitor use on the clinical efficacy of clopidogrel was found. In patients receiving concomitant atorvastatin and clopidogrel, the antithrombotic effect of clopidogrel was moderately attenuated, but the combination significantly reduced the overall mortality. CYP3A4 inhibitors and atorvastatin may reduce bleedings in clopidogrel users.

A building may have three types of flexibility: a) service flexibility is important to the building's users, b) modifiability interests especially the owner, and 3) long-term adaptability is a key factor especially in the stratification of the urban structure and the cultural environment. A new indicator, the Flexibility Degree, was developed as part of this study to measure building modifiability. Clear phasing of the design process facilitates consideration of modifiability in the construction process. In the goal-setting phase the design team analyzes the client's expressed needs and commits together with representatives of the client to set flexibility goals. In the design solution phase the designers work out a solution proposal, a modifiability concept, which describes the principles of how flexibility is implemented in different parts and systems of a building. Only in the third phase, the implementation design phase, are detailed technical plans drawn for implementing the solutions.

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