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Imidazole is a substance released by the organism when a new salicylate derivative, imidazole salicylate is administered. A study was made of the binding of imidazole to human serum albumin by an in vitro assay employing an ultrafiltration technique. For the concentration range that imidazole was found in plasma following administration of the drug to healthy volunteers, the mean binding percentages were: 12.1 +/- 1.8 and 19.7 +/- 3.1 at 37 degrees C and 25 degrees C, respectively. The results obtained in the study follow a model entailing three equal and independent binding sites of imidazole to serum albumin and the values of the corresponding constants were determined. Apparently, the presence in the plasma samples of sodium salicylate at a concentration of 100 micrograms/ml does not affect the binding of imidazole to human serum albumin.

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The pharmacokinetics of fosmidomycin in phase I with a total of 127 healthy male volunteers is described through single--and repeated--dose studies using oral and parenteral routes of administration. The study results indicate that fosmidomycin is well tolerated even when given in repeated doses of 8 g/day i.v. for 7 days, 4 g/day i.m. for 5 days, and 4 g/day p.o. for 7 days. The gastrointestinal absorption rate after oral dosing of 500 mg is in general about 20-40%, which can be calculated to be on average about 30% (in comparison with fosfomycin which is on average only about 11%). Absorption seems to be slow and moderate. In the single-dose studies, the mean peak serum concentrations were 2.45 micrograms/ml and 12.3 micrograms/ml after 500 mg p.o. and 7.5 mg/kg (ca. 500 mg) i.m. doses respectively. The mean concentration after 15 mg/kg (ca. 2.2 g) i.v. dose was 157 micrograms/ml at 0.25 h. The serum half-lives were 1.65 h, 1.58 h and 1.87 h after i.v., i.m. and p.o. doses respectively. The recovery rate in urine was 85.5%, 66.4% and 26% after i.v., i.m. and p.o. doses respectively. In repeated-dose studies, no serum accumulation could be observed after 1 g q6h for 5 days, 1 g q6h for 7 days or 2 g q6h for 7 days. Mean peak serum levels of 34.0-35.5 micrograms/ml were recorded at steady state. The serum protein binding found in man was less than 1%. Unmetabolized fosmidomycin was the only bioactive substance found in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

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Imidazole 2-hydroxybenzoate is a novel nonsteroidal antiinflammatory agent which clinico-pharmacologically and pharmacokinetically has to be understood as imidazole and salicylic acid. The pharmacokinetic profile of both components after single and multiple oral (tablets, drops), and topical administration (gel 5%)--the latter in a pilot study--was evaluated as well as protein-binding, relative bioavailability and the metabolic pattern. Absorption and elimination of the two compounds were fast. All essential pharmacokinetic and bioavailability parameters seem to be in a good agreement with data published in the literature and an accumulation tendency was not observed. The t1/2 beta for imidazole (oral administration) was determined for a single dose at 2.98 +/- 1.13 h, for a multiple dose (last dose) at 1.86 +/- 0.78 h; for salicylic acid the t1/2 beta for a single dose was determined at 6.46 +/- 3.79 h and for a multiple dose (last dose) at 6.40 +/- 3.36 h. The protein-binding of imidazole was in the range of 5-15% and of salicylic acid of about 80-85%. The relative bioavailability was calculated for imidazole (single dose) at 138% and for multiple dosing (last dose) at 113%; for salicylic acid the values for single dose were 148% and for multiple dosing (last dose) 128%. The tolerability was altogether good and no adverse reactions could be observed. The topical administration (pilot study) with gel 5% did not show any systemic effects or adverse reactions. The local tolerability was very good. Statistically, there were only slight differences between tablets and drops overall since only one p-value was less than 0.01. According to the small sum of squared residuals, the NONLIN-program performed an excellent fitting of the data to the model equation.

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The pharmacokinetics of fosmidomycin in phase I with a total of 127 healthy male volunteers is described through single and repeated dose studies using oral and parenteral routes of administration. The study results indicate that fosmidomycin is well tolerated even when given in repeated doses of 8 g/day i.v. for 7 days, 4 g/day i.m. for 5 days, and 4 g/day p.o. for 7 days. The gastrointestinal absorption rate after oral dosing of 500 mg is in general about 20-40% which can be calculated to be, in average, about 30% (in comparison with fosfomycin which is, in average, about 11% only). The absorption seems to be slow and moderate. In single dose studies, the mean peak serum concentrations were 2.45 micrograms/ml and 12.3 micrograms/ml after 500 mg oral and 7.5 mg/kg (ca. 500 mg) i.m. doses, respectively. The mean concentration after 15 mg/kg (ca. 2.2 g) i.v. dose was 157 micrograms/ml at 0.25 h. The serum halflives were 1.65 h, 1.58 h and 1.87 h after i.v., i.m. and p.o. doses, respectively. The recovery rate in urine was 85.5%, 66.4% and 26% after i.v., i.m. and p.o. doses, respectively. In repeated dose studies, no serum accumulation could be observed after 1 g q6h for 5 days, 1 g q6h for 7 days or 2 g q6h for 7 days. Mean peak serum levels of 34.0-35.5 micrograms/ml were recorded at steady state. The serum protein binding could be found in man less than 1%. Unmetabolized fosmidomycin was the only bioactive substance found in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

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The pharmacokinetics of fosmidomycin in phase I with a total of 127 healthy male volunteers is described through single and repeated dose studies using oral and parenteral routes of administration. The study results indicate that fosmidomycin is well tolerated when even given in repeated doses of 8 g/day i.v. for 7 days, 4 g/day i.m. for 5 days, and 4 g/day p.o. for 7 days. The gastrointestinal absorption rate after the oral dosing of 500 mg is in general about 20-40% which can be calculated to be in average about 30% (in comparison with fosfomycin which is in average about 11% only). The absorption seems to be slow and moderate. In single dose studies, the mean peak serum concentrations were 2.45 micrograms/ml and 12.3 micrograms/ml after 500 oral and 7.5 mg/kg (ca. 500 mg) i.m. doses respectively. The mean concentration after 15 mg/kg (ca. 2.2 g) i.v. dose was 157 micrograms/ml at 0.25 h. The serum halflives were 1.65 h, 1.58 h and 1.87 h after i.v., i.m. and p.o. doses respectively. The recovery rate in urine was 85.5%, 66.4% and 26% after i.v., i.m. and p.o. doses respectively. In repeated dose studies, no serum accumulation could be observed after 1 g q6h for 5 days, 1 g q6h for 7 days or 2 g q6h for 7 days. Mean peak serum levels of 34.0-35.5 micrograms/ml were recorded at steady state. The serum protein binding could be found to be less than 1% in man. Unmetabolized fosmidomycin was the only bioactive substance found in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

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Imidazole 2-hydroxybenzoate is a new antiphlogistic compound with analgesic and antipyretic properties undergoing clinical investigations. The purpose of this pilot study was to evaluate new methods for the quantitation of imidazole, salicylic acid and salicyluric acid in plasma and urine. Imidazole metabolites caused considerable methodologic difficulties in plasma and urine. They were below the detectable limit. Salicylic acid metabolites were present in plasma also under the limit of detection (0.5 microgram/ml). In urine the metabolite salicyluric acid was measured in considerable quantities, whereas gentisinic acid was under the limit of detection. Three healthy volunteers were given a single p.o. dose of 750 mg imidazole 2-hydroxybenzoate in order to examine the practicability of these new methods a well as to evaluate the pharmacokinetics. The data are presented and interpreted. Further studies in this respect are advised.

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The clinical pharmacology of lipid-lowering agents and their meaning in the treatment of the fat metabolism-atherosclerosis functional circle are described. All the aspects associated with these important problems are carefully analyzed and the possible consequences for their rational use are interpreted. The current view of the actual situation in this field is presented and the trends in the development of prophylactic and therapeutic treatment with lipid-lowering agents in the fat metabolism-atherosclerosis functional circle are shown. Epidemiologic considerations complement these reflections.

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The investigational drug, (dl)-3, 7-dihydro-1, 8-dimethyl-3-(2-methylbutyl)-1 H-purine-2, 6-dione, has been proven to be an active bronchodilator and antiallergic compound in animal and clinical studies. Adult asthmatic patients who demonstrated greater than or equal to 20% improvement in FEV1 after inhalation of aerosolized isoproterenol or its equivalent and greater than or equal to 20% reduction in FEV1 after a graded treadmill exercise received theophylline (3, 6 mg/Kg, every 6 h) for 4 days. Further selection of patients was made by demonstrating that theophylline effectively blocked exercise-induced reduction in FEV1 and was effective in increasing FEV1 by 20% when measured 2 h after oral administration. Thus, these adult asthmatics entered a double-blind, placebo-controlled, two-dose cross-over study with the investigational drug at dosage 0.075 mg/kg twice daily and 0.125 mg/kg twice daily. At both dosages studied the investigational drug was found to be an effective bronchodilator in blocking exercise-induced reduction in FEV1 by improving asthma disability scores and increasing FEV1 2 h after oral administration. The incidence and severity of the side effects observed were less than those observed with theophylline.

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In 40 patients, a seven day observation period in which oral bronchodilators and corticosteroids were eliminated, cetiedil (100 mg, t.i.d.), theophylline (200 mg, t.i.d.) or orciprenaline (20 mg, t.i.d.) and placebo (100 mg Lactose, t.i.d.) were given for one week each, according to a double blind, crossover randomized code. Wheezing scores were improved by all three active drugs. Twenty five of these patients undertook a moderate degree of exercise. Cetiedil was the most effective drug in blocking exercise-induced bronchospasm of the drugs studied. At rest, FEV1/VC was improved by theophylline, while PEFR improved after orciprenaline. Cetiedil improved both parameters, significantly. In another 21 patients, cetiedil (100 mg, t.i.d.) was given, according to the 'patient blinded' method for two weeks. PEFR and Asthma Disability Scores steadily improved. Clinical effectiveness was observed as early as the 3rd or 4th day of cetiedil therapy, with maximum improvement detected on the 14th day. No major side effects or abnormalities in clinical laboratory tests were noted. Cetiedil also had a 'liquidifying effect' on bronchial mucous in these asthmatics.

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