Synergism of ciprofloxacin (CPFX) and roxithromycin (RXM) to bacterial biofilms formed by Pseudomonas aeruginosa was investigated. Measurement of antibacterial activities and morphological observation with a scanning electron-microscope suggested that RXM eradicated the biofilms by unknown mechanism and thereby enhanced the bactericidal activity of CPFX to P. aeruginosa in biofilms.

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In order to evaluate antimicrobial activity of cefmenoxime (CMX), minimum inhibitory concentrations (MICs) of CMX and control drugs were determined against clinical isolates from patients of sinusitis that were obtained in our laboratory from October of 1993 to March of 1994. The results are summarized as follows;
1. CMX showed strong antimic robial activities against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella subgenus Branhamella catarrhalis that were 3 major aerobic b acteria from sinusitis. Antimicrobial activities of CMX against benzylpenicillin (PCG)-insensitive S. pneumoniae (PISP) and PCG-resistant S. pneumoniae (PRSP) were stronger than those of ampicillin (ABPC), and these strong activities suggested that CMX might have strong antimicrobial activities against β-lactamase producing H. influenzae and M.(B.) catarrhalis.
2. Antimicrobial activities of CMX against microaerophiles, Streptococcus constellatus, Streptococcus intermedius and Gemella morbillorum and against Peptostreptococcus spp., from chronic sinusitis and odontogenic maxillary sinusitis, were stronger than those of most of the control drugs.
3. The MIC90's of CMX against isolates from patients of sinusitis were≤0.025-0.39μg/ml. These values were lower than transitional concentrations in mucous membrane of maxillary sinus obtained when “1% CMX nasal solution” was used with nebulizer. It appears likely that sufficient concentrations exceeding MICs against main organisms would be obtained by nebulizer treatment using CMX nasal solution.

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A microbiological assay method for measurement of T-3761 and its stability in body fluids were investigated.
The paper disc method proved suitable for this assay using Escherichia coli Kp as a test organism and commercially available heart infusion agar as a test medium.
When using the paper disc method, lower detection limit of T-376 1 was approximately 0.05μg/ml and 0.1μg/ml for 1/15M phosphate buffer (pH7.0) and human serum, respectively.
T-3761 in human serum and urine was stable under freezing-20°C for at least 28 days.

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A high-performance liquid chromatographic procedure was develop ed for determination of T-3761 in human serum and urine.
The method was based o n column switching for serum, and direct injection for urine. The peaks were monitored by ultraviolet detection. The calibration curve was linear and quantitative in the concentration range of 0.01-30μg/ml for serum and 0.5-900μg/ml for urine. The intra-assay coefficient of variation was less than 7%. The intra-day and inter-day coefficient of variation were less than 4%.

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We studied the absorption, distribution, metabolism and excretion of T-3761, a new quinolone derivative, in experimental animals. The following results were obtained.
1. The peak serum levels of T-3761 after a single oral administration to various fasting animals at a dose of 5mg/kg were high in the order of rats, dogs, mice and rabbits, showing favorable absorption in all animals except for rabbits. In mice and rats, T-3761 showed higher peak serum levels than ofloxacin and ciprofloxacin but T-3761 were more rapidly eliminated from serum than ofloxacin and ciprofloxacin.
2. Tissue conce ntrations of T-3761 in rats were similar to those of ofloxacin but its ratio of tissue to serum levels were lower than those of ofloxacin.
3. Urinary excretion of T-3761 as active f orm until 24 hours after oral administration was 27.3%, 63.1%, 41.0% and 63.3% in mice, rats, rabbits and dogs, respectively. Only unchanged T-3761 was detected as active form in urine of all animals tested. In rats, urinary concentrations until 2 hours after administration were higher than those of ofloxacin.
4. Biliary excretion of T-3761 in mice and rats we re 2.9% and 1.4% as active form.
5. The absorption of T-3761 was not different in male and female rats or 8 and 1 4 weeks old rats. The meal lowered absorption of T-3761 in rats. There was no significant difference in serum levels, urinary excretion and distribution to tissues after multiple administration of T-3761 comparing with its single administration.
6. In rats with liver dysfunction induced by D-galactosamine, the serum levels and urinary excretion were slightly higher than in normal rats. On the other hands, in rats with kidney dysfunction induced by HgCl2, the serum levels were significantly higher and urinary excretion of T-3761 was significantly lower than in normal rats.
Above results show that T-3761 has uniq ue characteristics in absorption, excretion and distribution after oral administration to animals among new quinolones, i.e., T-3761 was eliminated rapidly and poorly distributed to tissues but showed superior absorption and high peak serum levels.

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We investigated the extent of the binding of T-3761 to serum protein and obtained the following results.
1. The binding rates of T-3761 to serum protein from various animals and human were 16.9-27.7%, and a little higher than those of ciprofloxacin and ofloxacin.
2. The binding rates of T-3761 to human serum protein were 19.1-23.8% at concentrations of 0.25-20μg/ml.
3. The binding rates of T-3761 lowered as the decrease of protein concentration.
4. The binding rates of T-3761 (2μg/ml) to human serum protein we re 12.4, 21.3 and 32.1% at pH7.0, 7.4 and 8.0, respectively, showing the effect of the pH.
5. The binding of T-3761 to human serum protein was re versible.
6. In vivo binding rates of T-3761 in rabbits after a sing le oral administration of 20mg/kg were 26.1-33.2%, which were similar to those obtained in vitro.

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The mechanism of the renal excretion of T-3761, a novel oral fluoroquinolone agent, was studied by renal clearance, stop-flow techniques and analyzing the pharmacokinetics with and without probenecid in rabbits, and which were compared with those of ofloxacin (OFLX).
In rabbits probenecid treatment induced increases in the elimination half-life (2.1 times higher) and area under the serum concentration-time curve (3.1times), and decreases in elimination rate constant (0.44times) and total body clearance (0.35times), while volume of distribution showed no significant change. In the stop-flow pattern, a specific peak of T-3761 was observed at the peak of p-aminohippuric acid (PAH), however, no specific trough of T-3761 was observed. On the other hand, a peak of OFLX was observed at the peak of PAH and a small trough at the trough of sodium. And the renal clearance of T-3761 and OFLX were about 4.9 and 3.3 times higher than the corresponding Cl_cr, respectively.
These results su ggested that T-3761 was excreted into urine by both glomerular filtration and renal tubular secretion, and was scarcely reabsorbed at distal tubule. The short elimination half-life of T-3761 might be explained by its great ratio of tubular excretion.

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The metabolism of T-3761 in mouse, rat, rabbit, dog and monkey was studied.
Four metabolites, other than unchanged T-3761, were detected and identified as follows: T-3761 glucuronide; T-3761M1, adduct of glucose; T-3761M2 and T-3761M3, compounds metabolized at 1-aminocyclopropyl ring.
In urine of mou se, T-3761 glucuronide was mainly detected, but in urine of other animals, T-3761 was mainly detected.

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The affinity of T-3761 to melanin was examined with synthetic melanin comparing other quinolones. The binding rates with synthetic melanin were from 37% to 48% for tosufloxacin, sparfloxacin, ciprofloxacin and norfloxacin. Binding rate of ofloxacin at 28% was lower and T-3761 was lowest at 22%.
Intraocular dynamics of T-3761 and ofloxacin were investigated in pigmented rabbits after a single oral administration at a dose of 20mg/kg. In both drugs, the concentrations in the melanin bearing tissues were higher and the disappearances from the melanin bearing tissues were more slowly than those of the non-melanin bearing tissues. T-3761 concentrations in the melanin bearing tissues were significantly lower than ofloxacin.
In vitro uptake amount to melan in bearing tissue of ofloxacin was 1.4-2.4 times larger than that of T-3761.

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Absorption, distribution, excretion and metabolism were studied in rats and mice after oral and intravenous administration of 5mg/kg of [¹⁴C] T-3761.
1. [¹⁴C] T-3761 was rapidly absorbed after oral administration and maximum serum concentration of radioactivity was observed at 15 min. and at 10min. in rats and mice, respectively. After that, radioactivity of serum declined rapidly.
2. The administered radioactivity was excreted mainly in the urine in rats and mice and excretion rate was 84% and 74%, respectively. The residual radioactivity was excreted in the feces. In both species, the urinary excretion rate after oral administration was similar to that after intravenous administration, suggesting that [¹⁴C] T-3761 was absorbed almost completely.
3. In the rat urine, over 90% of excreted radioactivity was T-3761. On the other hand, about 57% of excreted radioactivity was presumed to be glucuronide conjugate of T-3761 in the mice urine.
4. The biliary excretion of radioactivity in rats after oral administration was approximately 22%, and about 83% of those was presumed to be glucuronide conjugate. About 40% of the excreted radioactivity was reabsorbed from the intestinal tract.
5. Except gastrointestinal tract, tissue concentration of radioactivity after oral administration was high in kidney and liver. Radioactivity was widely distributed in other tissues at lower concentration than in the plasma, whereas hardly distributed in brain and spinal cord.
6. Whole body autoradiograms in rats indicate that radioactivity w ere widely distributed except central nervous systems.
7. The extent of the binding of [¹⁴C] T-3761 to serum protein was 23-31% and 25-34% in rats and mice, respectively.

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Placental transfer and mammary excretion of radioactivity were investigated in the pregnant rats on day 19 of pregnancy, in the pregnant mice on day 18 of pregnancy, and in the lactating rats after oral administration of 5mg/kg of [¹⁴C] T-3761.
1. Transfer of radioactivity to fetus was observed in rats and mice and the concentration in fetus was 0.2-0.5 times higher than in maternal plasma.
2. The radioactivity was excreted into the milk and the concentration in milk was higher than those of blood levels (milk/blood=1.3-5.8). The radioactivity in milk declined more slowly than in blood.

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General pharmacological effects of T-3761, a new oral quinolone antibacterial agent, on the central nervous system were investigated in laboratory animals. The results obtained are summarized as follows.
1. T-3761 exerted no significant effects on spontaneous motor activity, motor coordination, pentobarbital-induced hypnosis, electroshock-, pentetrazole-or strychnine-induced convulsion, acetic acid-induced writhing respones, reserpine-induced hypothermia and ptosis in mice at oral doses of 100,300 and 1,000mg/kg. The same oral doses of T-3761 exerted no significant effects on body temperature and passive avoidance response in rats.
2. T-3761 had no effects on EEG in cats and spinal reflex in rats at intravenous doses of 10, 30 and 100mg/kg.
3. Convulsions were not observed in mice after any oral combinations of T-3761 at a dose of 200 or 1,000mg/kg with 14 different nonsteroidal anti-inflammatory drugs (NSAIDs) including fenbufen.
4. An oral combination of T-3761 even at a higher does of 3,000mg/kg with 4-biphenylacetic acid (BPAA) which is a principally active metabolite of fenbufen also did not induce convulsions in mice
5. T-3761 did not inhibit GABA receptor binding in rat brain synaptic membranes at 10^-4M in either the absence or presence of BPAA.
These results suggest that T-3761 is an antibacterial agent which would be unlikely to produce any side effects on the central nervous system and to produce convulsion when combined with NSAIDs in clinical use.

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General pharmacological effects of T-3761, a new oral quinolone antibacterial agent, on the respiratory and cardiovascular systems, autonomic nervous system and other functions were investigated in laboratory animals. The results obtained are summarized as follows.
1. Respiratory and cardiovascular systems:
Oral administration of T-3761 at d oses of 100-1,000mg/kg did not affect in conscious rats. But intravenous administration of T-3761 at doses of 10-100mg/kg caused an increase in respiratory rate, induced hypotension, caused increase or decrease in heart rate and altered ECG patterns (elevation of T waves and reduction of voltage of QRS complexes, etc.) in anesthetized dogs. Intravenous administration of T-3761 at doses of 10-100mg/kg showed respiratory rate increase or decrease, hypertension, heart rate decrease and ECG patterns changes (T waves elevation and extrasystole) in anesthetized rabbits.
2. Autonomic nervous s ystem and smooth muscle organs:
T-3761 increased the epinephrine-induced contraction of the isolated guinea pig was deferens at concentration of 10^-5-10^-4g/ml. T-3761 decreased the acetylcholine-induced contraction of the isolated guinea pig ileum and epinephrine-induced relaxation of the isolated guinea pig trachea-chain at concentration of 10^-4g/ml. T-3761 increased the norepinephrine-induced contraction of the isolated rabbit thoracic aorta at concentration of 10^-4g/ml. Oral administration of T-3761 at a dose of 1,000mg/kg exerted slight mydriasis in mice.
3. Digestive system:
T-3761 decreased the spontaneous motilities of isolated ileum and colon at concentration of 10^-4g/ml. Oral administration of T-3761 at a dose of 1,000mg/kg inhibited gastric output and intestinal transit time in rats or mice.
4. Renal functions:
Oral administr ation of T-3761 at a dose of 300mg/kg increased Na⁺ excretion but did not affect PSP excretion in rats.
5. Hematological ex aminations:
T-3761 showed no effects on resistance to hemolysis, blood coagulation and platelet aggregation in rabbits at concentration of 10^-6-10^-4g/ml. Oral administration of T-3761 at dose of 100-1,000 mg/kg did not affect bleeding time or blood glucose level in rats.
6. Miscellaneous effects:
Intravenous administra tion of T-3761 at a dose of 100mg/kg slightly inhibited the twitch tension of gastrocnemius in anesthetized rats. Oral administration of T-3761 at doses of 300-1,000mg/kg exerted slight augmentation of carrageenin-induced hind paw edema in rats.
From these results, it can be assumed that T-3761 has a wide safety margin as an oral antibacterial agent

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