The standard checkerboard titration for detecting synergy between antibiotics is practicable for combinations of two antibiotics, laborious for combinations of three, and not feasible for combinations of four or more. Nevertheless, methods for testing of combinations of several antibiotics are urgently needed because some combinations might be superior to those in use and enable the successful treatment of infections resistant to current therapy. A simple method for measurement of synergy (or antagonism) with combinations of any number of agents has been developed which requires less effort than the standard checkerboard titration of two agents. With this method, the concentrations of each of n agents producing some specified effect (such as minimal inhibitory concentration or minimal bactericidal concentration) are determined. A reference combination made up of 1/n of each of these concentrations is titrated to find a dilution that produces the specified effect. The degree of dilution required is equal to the sum of the fractional inhibitory concentrations (concentration of each agent in combination/concentration of each agent alone) as conventionally determined by checkerboard titrations; sums of less than 1, 1, and greater than 1 indicate synergy, additivity, and antagonism, respectively.

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Four new hydroporphyrins [the o, m and p isomers of 5,10,15,20-tetra(hydroxyphenyl)chlorin and 5,10,15,20-tetra(m-hydroxyphenyl)bacteriochlorin] related to the tetra(hydroxyphenyl)porphyrins have been prepared. They show the expected strong absorption bands in the red region of the visible spectrum and are found to be very effective tumour photosensitizers.

Summary Four patients underwent intraoperative photodynamic therapy after surgery with meso-tetra-(hydroxyphenyl)-chlorin (mTHPC-PDT) for diffuse malignant mesothelioma. Preliminary procedures were performed in two patients in order to establish the efficacy of mTHPC-PDT and to optimise its tumoricidal effect. The (Faber, 1988). Improved local control does require additional measures, but the disease responds poorly to radio-and chemotherapy (Lerner et al., 1983). As photodynamic therapy (PDT) has been reported to be effective in human mesothelioma xenografts (Feins et al., 1990), it might allow for an appropriate 'clean-up' of the thoracic cavity after surgery. For clinical purposes, the currently used sensitisers for PDT are haematoporphyrin derivatives (HpD) and dihaematoporphyrin ether (DHE) . However, PDT with meso-tetra-(hydroxyphenyl)-chlorin (mTHPC) was superior to DHE-PDT with respect to antitumour activity and tissue selectivity in rodents without causing significant toxicity (Berenbaum, 1989). mTHPC might therefore be better fitted to large surface PDT as required for diffuse malignant mesothelioma treatment. A pilot study was done to evaluate mTHPC-PDT for diffuse malignant mesothelioma with respect to its antitumour activity and the feasibility of a combined modality approach under clinical conditions. Patients and methodsFour patients underwent mTHPC-PDT for diffuse malignant mesothelioma. Each patient was informed in detail about the experimental nature of the procedure and consent was obtained from each patient and from the local Human Investigations Committee of our institution.The four men were aged 46 (patient 1), 48 (patient 2), 65 (patient 3) and 50 years (patient 4), all having had possible occupation related exposure to asbestos. The main symptoms at admission were dyspnoea due to pleural effusion, chest pain and loss of weight. There was no evidence of disease in the peritoneal and contralateral chest cavity on CT-scans at admission. The right side was involved in patients 1, 2 and 4 and the left in patient 3. Previous biopsies revealed an epithelial (Figure la), a biphasic (Figure 2a), a sarcomatous and a mixed type of mesothelioma in the four patients and was confirmed in every case by immunohistologic examinations.Preliminary PDT To establish the efficacy of mTHPC-PDT and to optimise its tumouricidal effect, preliminary PDT was performed in patients 1 and 2 prior to its definitive application. Modulations of mTHPC dose, light dose and of the time interval between mTHPC application and activation were tested. mTHPC (Scotia Pharmaceuticals Ltd, Guildford, UK) was dissolved in 20% ethanol, 30% polyethylene glycol 400 and 50% H20 and administered over 15 min i.v. through a bacterial filter under sterile conditions within 60 min of preparation. Argon-pumped dye laser light of 650 nm (Coherent Innova 200 and Dye CR 599, GMP SA, Lausanne, Switzerland) was delivered through a sterilised optical fibre on tumour areas of 3 cm diameter. The power at the end of the optical fibre was measured wi...