Thein vitroantibacterial activity of NM394, the active form of the prodrug NM441, was compared with that of norfloxacin (NFLX), ofloxacin (OFLX), ciprofloxacin (CPFX), tosufloxacin (TFLX) and sparfloxacin (SPFX). The results may be summarized as follows:
1) NM394 demonstrated broad-spectrum antibacterial activity against gram-positive and gram-negative bacteria.
2) The activity of NM394 against gram-positive clinical isolates was comparable to that of OFLX and CPFX. Against gram-negative isolates, NM394 showed antibacterial activity equal to that of CPFX, but showed the greatest activity for all compounds tested against a part of strainsEnterobacteriaceaeandPseudomonas aeruginosa.
3) NM394 showed bactericidal action at the MIC against a variety of clinical isolates.
4) The activity of NM394 was unaffected by inoculum size, but slightly decreased in the presence of magnesium ions.
5) The antibacterial and bactericidal activity of NM394 was unaffected by human serum.
6) The susceptibilities of bacteria to NM394 were slightly decreased by passage in the presence of a subMIC concentration of NM394.
7) NM394 strongly inhibited the supercoiling activities of DNA gyrase purified fromStaphylococcus aureus, Escherichia coliandP. aeruginosa.

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Thein vitroactivity of NM394, the active form of a novel oral prodrug type fluoroquinolone NM441, was compared with that of ofloxacin (OFLX), norfloxacin, ciprofloxacin, tosufloxacin, and sparfloxacin (SPFX). The MIC₉₀s of NM394 against clinical isolates ofStaphylococcus aureus, methicillin-resistant S. aureus (MRSA), high-level MRSA, coagulase-negative Staphylococci, Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, Escherichia coliCS2 (R⁺), Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Citrobacter freundii, Serattia marcescens, Enterobacter cloacae, Pseudomonas aeruginosa (1987), P. aeruginosa (1991), Burkholderia cepacia, Stenotrophomonas maltophilia, Acinetobacter calcoaceticus, Haemophilus influenzae, andBacteroides fragiliswere 25, 1.56, 100, 0.39, 0.39, 1.56, 1.56, 1.56, 0.2, 0.1, 0.1, 0.025, 0.2, 25, 0.39, 1.56, 0.39, 1.56, 1.56, 12.5, 6.25, 3.13, 0.05, and 25μg/ml respectively. NM394 showed a broad antibacterial activity against both gram-positive and gram-negative bacteria. Against most species ofEnterobacteriaceae, NM394 showed superior activity to the other tested quinolones. The synergistic bactericidal effect of NM394 with mouse cultured macrophages was comparatively weak; the cells ofE. coliwere engulfed and digested by mouse cultured macrophages in the presence of greater than 1/2 MIC of NM394. The cytostatic activity of NM394 against CHO-K1, HeLa and IMR-32 mammalian cultured cells was greater than that of OFLX, and was similar to that of SPFX.

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The antibacterial activity of NM441, a prodrug of a new quinolone NM394, was compared with those of ofloxacin (OFLX), ciprofloxacin (CPFX), tosufloxacin (TFLX) and sparfloxacin (SPFX) in vitroandin vivo.
NM394 had the activity against gram-positive and-negative bacteria as other drugs, and againstPseudomonas aeruginosathe bactericidal activity of NM394 at sub-MIC was greater than those of OFLX, CPFX, TFLX or SPFX. On respiratory tract infection caused byKlebsiella pneumoniaeand on urinary tract infections caused byEscherichia coliorP. aeruginosain mice, NM441 was equal to or more effective than the other drugs tested. The pharmacokinetics of NM441 in mice and the antibacterial activity of NM394 were reflected in the therapeutic effect of NM441in vivo. In addition, we examined the bactericidal activities of NM394 or CPFX with anin vitropharmacokinetic simulation system that simulates human serum concentrations of NM394 or CPFX respectively. AgainstP. aeruginosa, NM394 and CPFX showed strong bactericidal activities 1 hour after treatment, but the time until regrowth in NM394 was longer than that in CPFX.

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The antimicrobial activity of NM394, the active form of the oral quinolone NM441, was compared to that of seven other quinolones (norfloxacin (NFLX), ofloxacin (OFLX), levofloxacin (LVFX), ciprofloxacin (CPFX), fleroxacin (FLRX), tosufloxacin (TFLX), sparfloxacin (SPFX)). The susceptibility testing by agar dilution method was carried out in 297 strains ofEnterobacteriaceae, 148 strains of glucose nonfermentative gram-negative rods, 270 strains of gram-positive cocci and 54 strains of anaerobes.
NM394 showed an almost equivalent acitivity to OFLX or CPFX against strains of streptococci andEnterococcusspp. NM394 showed the highest activity againstEnterococcus faeciumand the MIC_90% was 1.56μg/ml. NM394, however, showed lesser activity than LVFX, TFLX or SPFX against strains of staphylococci. The MICs_90%against methicillin-sensitive or methicillin-resistantStaphylococcus aureuswere 1.56 or 50μg/ml, respectively. Against strains ofEnterobacteriaceae, NM394 showed superior or equivalent activity to the reference quinolones and showed the highest activity against strains ofEscherichia coil, Citrobacter diversus, Klebsiella oxytoca, Enterobacter aerogenes, Proteus mirabilis, Proteus vulgarisandMorganella morganii. NM394 also showed the highest activity against strains ofPseudomonas aeruginosaandHaemophilus influenzaeand the MICs_90%were 0.39 and≤0.05μg/ml, respectively.
Thein vitropostantibiotic effect (PAE) of NM394 was evaluated. When strains ofE. coli, Klebsiella PneumoniaeorP. aeruginosawere exposed to NM394 at 2 MICs for 2hrs, the duration of PAE was 1.4, 1.8 and 1.9hrs, respectively, and NM394 tended to show an equivalent duration of PAE to NFLX, OFLX and CPFX.
Although NM394 alone had no bactericidal activity against the sessile cells of theP. aeruginosastrain formed on the Teflon sheet, NM394 showed synergistic bactericidal activity when combined with subMIC of erythromycin or clarithromycin.

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Thein vitroactivity of NM394, an active metabolite of a new quinolone NM441, was compared with those of ofloxacin (OFLX), ciprofloxacin (CPFX), tosufloxacin (TFLX), and fleroxacin (FLRX) against anaerobic bacteria and fastidious facultative anaerobes. NM394 had broad antibacterial spectrum against gram-positive and gram-negative reference strains of anaerobes, inhibiting most strains of anaerobic bacteria at 3.13μg/ml or less. NM394 had, however, weak activity againstClostridiumspp. and a part ofBacteroides fragilisgroup organisms. Susceptibility testing against fresh clinical isolates of anaerobic bacteria exhibited that NM394 was as active as CPFX and TFLX but more active than OFLX and FLRX againstPeptostreptococcusspp. and gram-positive rods and that NM394 was very potent against gramnegative anaerobic rods (MICs for 90% strains, 0.78μg/ml or less) except theB. fragilisgroup andPrevotella bivia, although NM394 had weak activity against theB. fragilisgroup. These results suggest that NM394 is as active as CPFX against anaerobic bacteria. Animal model experiments showed that NM441 did not provoke overgrowth ofClostridium difficilein the intestine of mice.

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NM441 is a prodrug of a 6-fluoroquinolone antibacterial agent. When NM441 was administered orally, it was readily absorbed and metabolized to its active form, NM394. Thein vitroandin vivoantibacterial activities of NM441 were compared with those of ofloxacin (OFLX), ciprofloxacin (CPFX), enoxacin (ENX) and tosufloxacin (TFLX). NM394 had a broad antimicrobial spectrum against gram-positive and gram-negative bacteria. The antibacterial activity of NM394 against clinical isolates of gram-positive and gram-negative bacteria was equal to or one-half that of CPFX. NM394 was as active as OFLX against gram-positive bacteria, and was 2 to 8 times more active against gram-negative bacteria, includingPseudomonas aeruginosa. The activity of NM394 was not influenced by the type of medium, inoculum size or addition of serum. The MICs of NM394 againstEscherichia coliandP. aeruginosaat pH 5.5 were reduced 4 to 16 times in comparison with those at pH7.0. The bactericidal activity of NM394 againstStaphylococcus aureus, E. coli, Serratia marcescensandP. aeruginosawas superior to those of CPFX, OFLX and TFLX. NM394 was accumulated to higher concentrations than OFLX and CPFX inS. aureus, E. coliandP. aeruginosa. In the morphological examination by the phase-contrast microscope, NM394 induced the formation of filamentous cell and lysis ofE. coliandS. marcescens, and induced the formation of spherical cell and lysis ofP. aeruginosa. The protective effect of NM441 against systemic infection caused by gram-positive and gram-negative organism in mice was superior to those of CPFX, OFLX and ENX.

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The in vitro postantibiotic effect (PAE) and in vivo effective regrowth time (ERT) of NM394, an active form of NM441, a new quinolone derivative, were studied.
The in vitro PAE of NM394 against Staphylococcus aureus Smith after exposure at the concentration of 2 and 4 MIC for 2 hrs was 0.85 and 0.95 hrs, respectively, which was slightly longer than that of ofloxacin (OFLX)(0.15 and 0.65 hrs, respectively).
The PAE of NM394 against Klebsiella pneumoniae BK after the exposure at the concentration of 0.25 μg/ml for 2 hrs was 3.15 hrs which was longer than that of OFLX (0.6 hrs), lomefloxacin (0.1 hrs) and fleroxacin (0.2 hrs).
The in vivo ERT of NM394 against K. pneumoniae BK in a neutropenic mice thigh infection model was 11.7 hrs (that of OFLX was 6.7 hrs) and that against Pseudomonas aeruginosa ATCC 27853 was 7.25 hrs which was longer than that of ciprofloxacin (4.0 hrs).

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The in vitro and in vivo antibacterial activity of NM441, a new prodrug type of quinolone derivative was compared with that of norfloxacin, ofloxacin (OFLX), ciprofloxacin (CPFX) and tosufloxacin (TFLX).
NM394, an active form of NM441, had broad spectrum of activity against gram-positive and gramnegative bacteria. The antibacterial activities of NM394 against gram-positive clinical isolates were inferior to those of TFLX but almost equal to or superior to those of OFLX and CPFX. Against gramnegative isolates, the activities of NM394 were equal to or superior to those of CPFX and TFLX and were clearly superior to those of OFLX.
The activity of NM394 was not affected by inoculum size, type of medium and horse serum, but decreased in acidic pH and in the presence of Al³⁺.
NM394 showed bactericidal effect aganist various bacteria more potent than that of OFLX and CPFX. The bactericidal effect was more apparent against gram-negative bacteria that viable cells were markedly reduced within 1-2h.
NM441 was less active than TFLX against systemic infections in mice with gram-positive bacteria, but was more effective than OFLX and CPFX against infections with streptococci. The ED₅₀s of NM441 against gram-negative bacteria were lowest among the drugs tested.
After oral administration of 50mg/kg of NM441, the maximum serum concentration of NM394 in mice was 3.06 μg/ml and the concentration ratios in lung and kidney were 1.3 and 5.6, respectively.

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The in vitro and in vivo antibacterial activity of NM441 against Pseudomonas aeruginosa was compared with that of the other quinolones. The results obtained may be summarized as follows:
1) The antibacterial activity of NM394 against clinical isolates of P. aeruginosa was equal to that of ciprofloxacin (CPFX). However, against quinolone-resistant strains, the activity of NM394 was slightly higher than CPFX.
2) NM394 showed bactericidal effect against P. aeruginosa at lower concentrations and more rapidly than the other quinolones.
3) NM394 also showed more rapid bactericidal effect than the other quinolones in medium containing human serum.
4) Postantibiotic effect (PAE) was not able to be calculated due to a strong bactericidal effect at concentrations higher than 2MIC of NM394. At a concentration of 1 MIC, PAE of NM394 was longer than ofloxacin (OFLX) and CPFX but shorter than tosufloxacin (TFLX).
5) NM441 showed greater therapeutic effects than OFLX, CPFX, TFLX and lomefloxacin (LFLX) against experimental urinary and respiratory tract infections in mice, and cutaneous infection in burnt mice.
6) On the subcutaneous pouch infection with P. aeruginosa in rats, the concentration of NM394 in pouch was lower than OFLX and higher than the other. NM441 showed the most rapid reduction of viable counts in pouch.

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New quinolones have been reported to have potent convulsant activity, and the concurrent administration of non-steroidal anti-inflammatory drugs (NSAIDs) has been reported to enhance this convulsant activity. We studied the effect of NM441, a newly developed quinolone, and NM394, an active metabolite of NM441, and its metabolites on the receptor binding of γ-aminobutyric acid (GABA), which is an inhibitory transmitter in the mammalian central nervous system (CNS). NM394 and NM441 inhibited GABA receptor binding in a concentration-dependent manner. The potency in the inhibition of the binding was between that of enoxacin and ciprofloxacin. In the presence of biphenylacetic acid (BPA), the inhibitory activity of NM394 was remarkably enhanced. The oxo-derivative and the ethylene-diamino-derivative inhibited GABA receptor binding, and their potencies were almost the same as NM394. But the inhibitory activity of the metabolites was little enhanced in the presence of BPA. These in vitro results suggest that NM394 induces convulsions through the inhibition of GABA receptor binding when it accumulates in the CNS, and that the concurrent administration of NSAIDs enhances the convulsant activity of NM394.

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Convulsant effects of NM441 were compared with those of ofloxacin (OFLX), ciprofloxacin (CPFX), lomefloxacin (LFLX) and enoxacin (ENX). These quinolones caused no convulsion in mice when orally treated alone, however, they elicited clonic and tonic convulsions and death by the combined treatment with fenbufen. The order of potency of their convulsant activity was ENX>LFLX>NM441>CPFX>OFLX. NM441 as well as other quinolones caused convulsions and death by the combined oral treatment with theophylline at the order of potency: LFLX≥OFLX≥ENX>NM441>CPFX. NM441 alone showed no potentiation of convulsant activities of bicuculline, pentetrazol and maximal electroshocks. Intravenous injection of NM394, an active metabolite of NM441, generated spike activities or seizure discharges from the thalamus and cerebral cortex in rabbits, and its effect was less significant than that of ENX and CPFX. Oral administration of NM441 showed no changes in the behavior and EEGs in rabbits. Spinal reflex potentials in cats were not affected by intravenous or oral treatments with NM394 or NM441, respectively. Binding of [³H] muscimol to the membrane preparations from rat brains was weakly inhibited by NM394 alone, and the inhibition was markedly potentiated in the presense of biphenylacetic acid, an active metabolite of fenbufen. The interaction of NM394 with GABA_A receptors may partly contribute to the convulsions caused by NM441.

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General pharmacological properties of NM441, a new quinolone antibacterial agent, were investigated in various species of animals. The following results were obtained.
1) General signs and gross behavior: NM441 at 1, 000mg/kg p.o. had no effect on general signs and gross behavior in mice.
2) Central nervous system: NM441 at 1, 000mg/kg p.o. slightly lowered yeast-induced fever in rats. At the same dose, it had no effect on locomotor activity, normal body temperature or conditioned avoidance response in rats. NM441 at 1, 000mg/kg p. o. had no effect on motor coordination, traction performance or hexobarbital-induced sleep, and had no analgesic or anticonvulsant effect in mice.
3) Peripheral nervous system: NM394, an active metabolite of NM441, at doses more than 3mg/kg i. v. suppressed nictitating membrane contractions induced by superior cervical pre-or post-ganglionic nerve stimulation and decreased blood pressure in anesthetized cats. NM441 at 1, 000mg/kg p. o. had no effect on pupil size in mice. NM441 (10^-4M) and NM394 (10^-3M) had no effect on contractions of isolated rat diaphragm induced by electrical stimulation of the phrenic nerve. NM441 (0.3%) and NM394 (1%) produced no local anesthesia in guinea-pigs.
4) Gastrointestinal tracts: Intraduodenally administered NM441 at 1, 000mg/kg had no effect on gastric secretion in pylorus-ligated rats. NM441 at 1, 000mg/kg p.o. had no effect on gastrointestinal transportation of charcoal meal in rats. At the same dose, it had no ulcerogenic activity in rat gastric mucosa.
5) Smooth muscle: NM441 at concentrations more than 3 × 10^-5M slightly decreased the motility of isolated rabbit ileum, but even at 10^-3M, NM394 did not. NM441 (10^-4M) and NM394 (10^-3M) had no effect on the motility of isolated rat uterus, and acetylcholine-, histamine-or Ba⁺⁺-induced contraction of isolated guinea-pig ileum, and noradrenaline-induced contraction of isolated rat vas deferens. NM441 (10^-4M) slightly relaxed isolated guinea-pig tracheal muscle, but had no effect on carbachol-induced contraction. NM394 (10^-3M) had no effect on tonus nor on carbachol-induced contraction of tracheal muscle.

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General pharmacological properties of NM441, a new quinolone antibacterial agent, were investigated in various species of animals. The following results were obtained.
1) Respiratory and cardiovascular systems: Intraduodenally administered NM441 at 100mg/kg slightly increased heart rate (HR), but had no effect on respiratory rate (RESP), mean blood pressure (MBP), electrocardiogram (ECG) and femoral arterial blood flow (FBF) in anesthetized dogs. NM394, an active metabolite of NM441, at doses more than 1mg/kg i.v. produced changes in ECGs (decrease or increase in the height of P, R and T, inversion of P and T) in anesthetized dogs, but had no effect on the PQ interval of ECGs nor on HR even at 10mg/kg i.v. At doses more than 3mg/kg i.v., it decreased MBP, and at 10mg/kg i.v. increased RESP and decreased FBF. NM394 at doses more than 3mg/kg i.v. decreased MBP, left ventricular pressure and left ventricular end diastolic pressure in anesthetized open chest dogs. At the same doses, it increased FBF and tended to decrease total peripheral resistance. NM394 at 10mg/kg i.v. decreased HR, cardiac output and dP/dt max. At the same dose, it decreased MBP and produced nonselective suppression to blood pressure response induced by carotid occlusion, acetylcholine or noradrenaline (NA) in anesthetized cats. NM394-induced decrease in MBP was suppressed by pre-treatment of cimetidine or diphenhydramine in anesthetized rats. But NM394 did not elicit constriction of airway in anesthetized guinea-pigs. NM394 at concentrations more than 3 × 10^-4M slightly suppressed the contraction of papillary muscle isolated from guinea-pig, but had no effect on the beating rate of the right atria even at 10^-3M. NM441 (10^-4M) had no effect on the beating rate of the right atria or on the contraction of the papillary muscle. NM394 suppressed NA-induced contraction of isolated rat aorta at concentrations more than 10^-4M and KCl-induced contraction at 10^-3M. NM441 (10^-4M) had no effect on NA-or KCl-induced contraction of isolated rat aorta.
2) Renal function: NM441 at 1, 000mg/kg p.o. had no effect on urine volume, urinary electrolyte (Na⁺, K⁺ and Cl^-) excretion, urinary pH or phenolsulfonphthalein excretion in rats.
3) Others: NM441 at 1, 000mg/kg p.o. suppressed carrageenin-induced paw edema in rats. At the same dose, it had no effect on blood glucose level in rats. Intraduodenally administered NM441 at 1, 000mg/kg had no effect on disappearance rate of plasma sulfobromophthalein (hepatic function) in anesthetized rats. NM441 at 1, 000mg/kg/day p.o. for 2 days had no effect on prothrombin time or activated partial thromboplastin time in rats. NM394 (10^-3M) suppressed collagen-induced aggregation of platelets taken from rabbits, but did not ADP-or arachidonic acid-induced aggregation. NM441 (10^-4M) and NM394 (10^-3M) had no hemolytic activity in rat red blood cells.

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The assay methods for determining the concentrations of NM394, the active compound of NM441, in body fluids were examined.
In high-performance liquid-chromatography (HPLC), the organic solvent extraction method and the solid-phase extraction method were found to be available for determining the concentration of NM394.
In bioassay methods, agar well method, cup method and paper disk method were found to be available when Escherichia coli Kp and sensitivity test agar were used.
NM394 concentrations determined by HPLC and bioassay method in human plasma and urine were well correlated.
In human plasma and urine, NM394 was stable for at least 4 weeks when stored in -20°C.

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The absorption of NM441 was studied in rats, rabbits, dogs and monkeys after intravenous injection and oral administration. The following results were obtained.
1) After oral administration of 20mg/kg of NM441, NM441 was not detected in blood.
2) After intravenous injection of 5mg/kg of NM394 and oral administration of 20mg/kg of NM441, the half-lives of the elimination phase (T_1/2, β) of NM394 were 2.07, 3.16, 4.96 and 12.0h in rats, rabbits, dogs and monkeys, respectively.
3)After oral administration of 20mg/kg of NM441, the plasma concentration of NM394 reached maxima at 1.0, 0.25, 1.5 and 4.0h in rats, rabbits, dogs and monkeys, respectively. Maximal concentrations in rats, rabbits, dogs and monkeys were 1.47, 0.78, 2.00 and 0.97μg/ml, respectively.
4) The bioavailability of NM441, calculated from the ratio of AUC values for plasma NM394 concentration after intravenous injection of NM394 and oral administration of NM441, was 38.9, 9.06, 42.2 and 24.9% in rats, rabbits, dogs and monkeys, respectively.

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The plasma and cerebrospinal fluid (CSF) concentrations of NM394, an active form of NM441, ciprofloxacin (CPFX) and tosufloxacin (TFLX) were studied in dogs.
1) The half-lives (T_1/2β) of each drug were 5.72h (NM394), 6.89h (CPFX) and 3.90h (TFLX).
2) The peak CSF concentration of each drug was obtained lh after administration and decreased at the same half-life as was observed with plasma.
3) The AUC ratios between plasma and CSF were NM394 (13.9%) <CPFX (20.7%)=TFLX (22.6%).

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Renal excretion mechanism of NM394, an active form of NM441, was studied in rabbits by stop-flow analysis methods. In addition, the pharmacokinetics of NM441 was studied in renal insufficient rats. The results may be summarized as follows:
1) NM394 is extensively secreted by the proximal tubules in addition to the glomerular filtration in rabbits.
2) Renal clearance of NM394 was greater than that of GFR in normal rats. Then, it was suggested that NM394 was also secreated by the proximal tubules in rats.
3) The plasma concentrations of NM394 in elimination phase after administration of NM441 were increased in HgCl₂ insufficient rats. T_1/2 and AUC were increased by 4.6 and 4 times compared to normal rats.
4) Cumulative renal excretions in renal insufficient rats were decreased to 14-22% compared to normal rats.

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Fecal microflora was inspected before, during and after oral administration of NM441, the prodrug of the new quinolone NM394, to two groups of beagle dogs (100mg/dog/day and 1, 000mg/dog/day, as NM394) at single dose per day for 14 consecutive days. We investigated the detecti0n of Clostridium diffile related antigen, the antibacterial activity of NM394 and the concentration of NM394 in the feces.
1) The feces of two groups each were normal during the experiment, and no changes such as diarrhea were observed.
2) The total aerobes and anaerobes counts during the experiment were not significantly changed. The count of Enterobacteriaceae remained under the detection limit, those at 7 days after administration were similar to those before administration.
3) The C. difficile related antigen was detected in 4 animals at 7 and 14 days after administration of the drug, but not detected 28 days post-administration.
4) The antibacterial activity of NM394 in the feces was low in all groups.
5) The resistant strains observed were Staphylococcus, Streptococcus and Bacteroides fragilis.

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The safety and pharmacokinetics of NM441, a prodrug of a new thiazeto-quinoline carboxylic acid derivative, NM394, were evaluated in healthy male volunteers given the drug orally in single doses of 20, 50, 100, 200 and 400mg, and multiple doses of 300mg twice daily for 6.5 days. No remarkable abnormalities were observed in symptoms, physical tests, laboratory tests, electrocardiogram (ECG), electroencephalogram (EEG) or equilibrium test. The mean plasma concentrations of active metabolite NM394 peaked between 0.5 and 1.0 hours, and the maximum concentrations were 0.68, 1.09 and 1.88/2g/ml at doses of 100, 200 and 400mg, respectively. The mean half-lives were 7.7 to 8.9 hours and were not affected by dose. The mean urinary excretion rates of NM394 were 46.0, 38.3 and 30.6% of the doses within 48 hours, respectively, and other metabolites were excreted in urine by 7% the doses. The salivary concentrations of NM394 were approximately 20% of the plasma concentrations. The mean fecal excretion rates of NM394 and NM441 were 52.9 and 4.2%, respectively within 72 hours after dosing of 400mg. The C_max, AUC and urinary excretion rates were not altered by food intake, whereas the T_max was prolonged slightly. In the multipledose study, the steady state of plasma concentration of NM394 was achieved on day 3 or 4, and further accumulation did not occur thereafter. The mean urinary excretion rate of NM394 was 49.0% during and 48 hours after the multiple administration. The acceptable safety and tolerance and defined pharmacokinetic characteristics of NM441 supports further testing.

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NM441, a newly developed prodrug type quinolone, was administered to 7 healthy adults at a dose of 200mg, twice a day for 8 days, to study the effects of this drug on the fecal bacterial flora, to determine the fecal concentration of NM394, which is the active form of NM441, and to examine the drug sensitivities of NM394 and other quinolones to various bacteria isolated from fecal samples. In addition, the pharmacokinetics and safety of NM441 were evaluated. The results were as follows.
1) Enterobacteriaceae temporarily decreased below the detection limits during the administration of the drug in all cases. The average number of other gram-negative bacilli and gram-positive cocci including Staphylococcus sp. and Enterococcus sp. also temporarily decreased during the administration. The total number of aerobes decreased during the administration. However, no constant change was noted in the average number of Yeast like organisms.
No changes were observed in the average number of Bifidobacterium and Bacteroides fragilis group, but the average number of Veillonella, Fusobacterium, and Lecithinase (+) Clostridium temporarily decreased during the course of drug treatment. No change was observed in the total number of anaerobes.
After the drug treatment, however, the fecal flora soon returned to their former levels.
2) Clostridium difficile was isolated from 2 cases from the first day of treatment to the 30th day after administration of drug, and D-1 antigen was detected the same day. One of the 2 cases showed a significant increase in neutralized antibody titer in the serum. Furthermore, D-1 antigen was detected in 2 other cases after administration. During administration, C. difficile and D-1 antigen were not observed in all cases.
3) The fecal concentrations of NM394 were 320-1, 491μg/g in all cases during the administration, and the highest fecal concentrations were determined at the end of the administration in 5 cases out of 7. After the administration of drug, the fecal concentration was below the limit of detection in 3 cases out of 7. In the other cases, NM394 was detected in 3 cases to the 3rd day after treatment and in 1 case to the 5th day after treatment.
4) The MICs of NM394 for some species of gram-positive cocci were similar to those of ofloxacin (OFLX), ciprofloxacin (CPFX) and sparfloxacin (SPFX). The MICs of NM394 against Escherichia coli and Enterobacter cloacae were equal or similar to those of CPFX, tosufloxacin (TFLX) and SPFX, less than those of OFLX or fleroxacin. The MIC of NM394 against Klebsiella pneumoniae was greater than that of CPFX and equal or similar to that of the other quinolones. The MIC of NM394 against Citrobacter freundii was similar to that of CPFX and less than that of the other quinolones. The MICs of NM394 against Bacteroides fragilis group were larger than those of TFLX and equivalent to those of the other quinolones.
5) The T_max, C_maxand AUC_0-12 of the 1st dose were almost equal to those of the last dose, no accumulation was observed. Each parameter and the urinary excretion rate were almost equal to those of the phase I study.
6) No side effects and no abnormal laboratory findings were observed.

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The influence of milk on absorption of NM441, a new prodrug type of quinolone antibiotic, was investigated in 6 healthy male volunteers.
Serum maximum concentrations (C_max) of NM394 (an active form of NM441) were 1.43±0.27μg/ml (Mean±SD) and 1.00±0.26μg/ml, and AUC_0-∞were 7.60±1.47μg·h/ml and 5.19±1.72μg·h/ml in theadministration of NM441 (200mg equivalent to NM394) with 200ml of water and milk, respectively, showing about 30% of significant decreases in administration with milk. The accumulated urinary excretion rates by 24h after administration were 43.9±5.8% and 30.8±5.4% in administration with water and milk, respectively, showing also about 30% of decreases in administration with milk. There were no large differences in T_max. and T_1/2.
From the above results, it was confirmed the administration of NM441 with milk decreases the absorption of this drug.

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We performed pharmacokinetic studies on NM441, a new quinolone, in the field of dentistry and oral surgery.
1) NM441 was administered to 10 healthy subjects before and after meal at 200mg, and the serum and the saliva concentrations of NM394 (an active form of NM441) were determined periodically.
A pharmacokinetic study was performed using a one-compartment model. The parameters of pharmacokinetic analysis were as follows.
Serum Saliva
Fasting Non-fasting Fasting Non-fasting
T_max(h) 0.85 1.52 2.23 2.38
C_max(μg/ml) 1.02 0.82 0.19 0.19
T_1/2(h) 2.73 3.47 3.05 3.24
AUC(μg·h/ml) 4.45 4.66 0.97 1.00
2) NM441 200mg was administered to 40 patients and the effusion of tooth extraction wounds of NM394 was measured when tooth was extracted. At 1-5 hour after administration, the concentration in the effusion of NM394 revealed 0.15-0.97μg/ml.

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The effect of NM441, a new quinolone derivative, on the serum concentration of theophylline was studied in 5 healthy male volunteers. A slow release preparation of theophylline at a daily dose of 400mg was given orally for 4 days prior to NM441 administration, and the serum level of theophylline was determined on the 4th day as the control. NM441 was then given orally at 200mg twice daily for 5 days with concomitant administration of theophylline.
On the third day of concomitant administration, the C_max and AUC were 1.21-fold and 1.17-fold higher respectively than those of the control. On the fifth day they were 1.24-fold and 1.21-fold higher than those of the control respectively, and the total body clearance of theophylline decreased by 16.1% relative to that of the control. No side effects were observed, but a slight abnormal change in the laboratory value of GPT was observed in 1 patient. From the above results, NM441 was considered to slightly increase the serum level of concomitantly administered theophylline, indicating an increase of a similar degree to that of ciprofloxacin and tosufloxacin.

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NM441 is a new prodrug type of pyridone carboxylic acid antibiotic.
MICs of its active form, NM394, against 216 clinical isolates of 7 species were examined. MIC₉₀ values against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), Escherichia coli, Klebiella pneumioniae, Serratia marcescens, Morganella morganii and Pscudomonas aeruginosa were determined to be 12.5, >100, 0.10, 0.10, 12.5, 0.10 and 3.13μg/ml, respectively. These values were almost equal to those of norfloxacin (NFLX), ofloxacin (OFLX), ciprofloxacin (CPFX), lomefloxacin (LFLX) and tosufloxacin (TFLX).
The clinical efficacy was studied in 17 patients with respiratory infections (9 with chronic bronchitis, 2 with pulmonary fibrosis+infection, 2 with pulmonary silicosis+infection, 1 with old pulmonary tuberculosis+infection, 1 with bronchiectasis+infection, 1 with bacterial pneumonia and 1 with mycoplasma pneumonia) by administering NM441 at a dose of 100-200mg twice a day for 7 to 14 days. The clinical efficacy rate was 88.2%, and causative organisms isolated from 9 cases were eradicated in 8 and partially eradicated in 1. Neither side effects nor abnormal laboratory findings were observed. From the above results, it was confirmed NM441 has excellent efficacy and safety.

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Basic and clinical studies on NM441, a new prodrug type quinolone, were performed and the following results were obtained.
1. In vitro antimicrobial activity
The minimum inhibitory concentrations (MICs) of NM394, the active form of NM441 were measured for 101 strains of 5 clinically isolated species and compared to those of ofloxacin (OFLX), ciprofloxacin (CPFX), tosufloxacin (TFLX) and sparfloxacin (SPFX). The activity of NM394 against Streptococcus pneumoniae was equal to that of CPFX but less than that of OFLX, TFLX and SPFX. NM394 showed better activity against Klebsiella pneumoniae than OFLX and SPFX and the activity was equal to that of CPFX and TFLX. The activity of NM394 against Haemophilus spp. was equal to that of OFLX, TFLX and SPFX but less than that of CPFX. NM394 showed better anti-pseudomonal activity against Pseudomonas aeruginosa than OFLX and the activity was equal to that of SPFX but less than that of CPFX and TFLX. None of them showed meaningful activity against Staphylococcus aureus.
2. The penetration into sputum and serum
NM441 was orally administered to a chronic bronchitis patient at a dose of 300mg twice a day for 5 days. The serum and sputum levels of NM394 were determined on the first, 3rd and 5th day of the administrations. The maximum serum levels were obtained 4 h after each administration on the first, 3rd and 5th days and the values were 1.43, 3.45 and 2.86μg/ml, respectively. The maximum sputum levels were obtained 6 h after the first and 3rd day of the administrations, but on the 5th day the peak was obtained in the first sputum in the morning, which was 1 h prior to the administration. Those values were 2.64, 7.49 and 6.40μg/ml, respectively. The penetration rate to the sputum was 185-224% higher than that to the serum.
3. Clinical efficacy
NM441 was administered to a total of 12 patients with respiratory tract infections at 100-300mg twice a day for 5-14 days. The clinical efficacy was evaluated as excellent in 1 acute pneumonia, good in 7 cases (1 mycoplasma pneumonia, 3 chronic bronchitis and 3 secondary infections to bronchial asthma), fair in 1 chronic bronchitis and poor in 3 cases (3 bronchiectasis). The clinical efficacy rate was 66.7%. No side effects were observed but abnormal laboratory findings were observed in 1 case in GOT·GPT elevation and in 1 case in ALP·γ-GTP·LAP elevation.

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The in vitro antimicrobial activity of NM394 was evaluated, and therapeutic efficacy of NM441, a new-quinolone agent for oral use developed in Japan which is a prodrug of NM394, were evaluated in the treatment of respiratory tract infections.
The minimum inhibitory concentrations (MICs) of NM394, ofloxacin (OFLX), ciprofloxacin, tosufloxacin and rifampicin against 20 strains each of methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Pseudomonas aeruginosa, 18 strains each of Enterobacter cloacae and Mycobacterium intracellulare, 22 strains each of Mycobacterium tuberculosis and Mycobacterium avium, and 3 strains of Haemophilus influenzae were determined by the micro-broth dilution method using the Dynatech MIC2000 system. As shown by MICs, NM394 was as active as OFLX against all the species tested except for K. pneumoniae and P. aeruginosa. NM394 was the most active against K. pneumniae and P. aeruginosa among agents tested.
Nine patients with pneumonia and 1 patient with diffuse panbronchiolitis received a dose of 100mg (3 cases), 200mg (6 cases) and 300mg (1 case) of NM441 twice a day per os for 10 to 14 days (mean; 13.6 days). The clinical effects were excellent in 2 and good in 8 patients (efficacy rate: 100%). Two strains each of Streptococcus pneumoniae and H. influenzae were identified as causative organisms. Three strains were eradicated and 1 strain of H. influenzae was persisted after therapy. No adverse reaction was observed during treatment with NM441. Transient elevation of serum transaminase was observed in 1 patient, but this adverse effect disappeared immediately after completion of therapy. We conclude from the above results that NM441 is one of the most useful quinolone agents for oral use as a drug of first choice in the treatment of respiratory infections.

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We carried out basic and clinical studies on NM441, and obtained the following results.
In the in vitro antibacterial activities, MICs of NM394 (the active form of NM441) were examined against gram-positive bacteria (methicillin-susceptible Staphylococcus aureus, methicillin-resistant S.aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus Pyogenes, and Streptococcus pneumoniae) and gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, indole-positive Proteus spp., Citrobacter freundii, Enterobacter cloacae, Pseudomonas aeruginosa, gentamicin-resistant P. aeruginosa, imipenem-resistant P. aeruginosa, Haemophilus influenzae and Moraxella catarrhalis) and compared with those of other new-quinolones (ofloxacin, ciprofloxacin and tosufloxacin (TFLX)), cefdinir, minocycline and amoxicillin. The activities of NM394 against grampositive bacteria were almost equal to those of the other drugs, and the activities of NM394 against gramnegative bacteria were equal to or better than those of TFLX.
In the clinical study, NM441 was administered to 29 patients, 13 cases with acute bronchitis, 9 with acute pharyngitis, 3 with acute tonsillitis, 3 with bronchial athma+infection and 1 with acute pyelonephritis (male: 11; female: 18; age: 16-78 years old), at a dose 100-200mg twice a day for 3-10 days. Clinical response was excellent in 5 cases, good in 19, fair in 4 and poor in 1. No side effects were observed, and abnormal laboratory findings were observed with slight increases in eosinophile in 2 cases.

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Pharmacokinetics and clinical studies were performed on NM441, a newly-developed prodrug type of quinolone antibiotic, and the following results were obtained.
1) Pharmacokinetics
The pharmacokinetics was investigated in 6 healthy volunteers administered 200mg of NM441 with or without several antacids or iron preparations by crossover method.
In the fasting state, 1g of dry aluminium hydroxide gel fine granule (Al), 500mg of magnesium oxide fine granule (Mg), 1g of precipitated calcium carbonate powder (Ca) or 50mg of ferrous sulfate tablet was orally administered at same time as NM441, while 200mg of cimetidine was administered at 1h before NM441.
A comparison of the effects of several antacids and iron preparations on the serum NM394 concentrations by C_max and AUC indicated the following results. Al, Mg, Ca, Fe and cimetidine decreased to 7, 39, 40, 15 and 33% of control C_max, and 15, 43, 45, 25 and 60% of control AUC, respectively. In addition Al, Mg, Ca, Fe and cimetidine decreased the urinary recovery rates of NM394 until 24h after administration to 7, 43, 51, 20 and 52%, respectively.
When Al, which showed the highest inhibition against absorbency and excretion of NM441 in this study, was administered at 3h or 2h before, or 1h or 2h after NM441 administration, the serum NM394 concentration showed 60, 64, 106 or 90% of control C_max, and 65, 54, 87 or 82% of control AUC, respectively. The urinary recovery rate of NM394 until 24h after administration decreased to 52, 20, 87 or 81%, respectively.
From above results, the absorbency of NM441 was inhibited by the concomitant use of antacids or iron preparations and the order of inhibition was Al>Fe>Mg>Ca>cimetidine. However, it was considered that the inhibition was mild when administered at 1h after NM441 administration.
2) Clinical results
NM441 was orally administered to a total of 4 patients, 1 with chronic bronchitis, 1 with tuberculous pleurisy and 2 with urinary tract infections, at a daily dose of 200 or 400mg for 5-10 days. In the clinical efficacy, 3 patients were able to be evaluated, and all of them were evaluated as good or excellent. No side effects were observed in all cases. Abnormal changes in laboratory findings were observed in the increase of platelet in 1 case and in the elevation of GPT in 1.

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The influence of concomitant administration with probenecid on pharmacokinetics of NM441, a new quinolone antibiotic, was investigated by a crossover method of 200mg NM441 administration with or without 1.5g probenecid in 6 healthy male volunteers.
AUC_0∞ of NM394 (an active form of NM441) was increased by the concomitant administration with probenecid from 6.67μg·h/ml to 9.75μg·h/ml, and t_1/2β was prolonged from 6.3h to 10.1h. CLtot/F was decreased from 33.43L/h to 23.25L/h, and also the urinary excretion was decreased by 57%.
From the above results, the influence of concomitant administration with probenecid was observed on the plasma concentration and urinary excretion of NM394, and it was suggested that the renal excretion of NM394 was related to renal tubular secretion in addition to glomerular filtration.
In the clinical study, NM441 was administered to 1 patients with pneumonia at a dose of 200mg twice a day for 14 days. The clinical response was good, and isolates before treatment, Staphylococcus aureus and Peptostreptococcus micros, were eradicated. No side effects were observed.

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We investigated the antibacterial activities and clinical efficacy of NM441, a newly-developed quinolone antibiotic, and the following results were obtained.
1) Antibacterial activities
The antibacterial activities of NM394 (active form of NM441) against 150 strains of 6 species were measured. MIC₉₀s of NM394 against methicillin-susceptible Staphylococcus aureus (MSSA), methicillinresistant S. aureus (MRSA), Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Pseudomonas aeruginosa were 3.13, 6.25, 0.1, 0.2, 0.39 and 3.13μg/ml, respectively.
2) Clinical results
Subjects in the clinical study were a total of 10 patients including 5 cases with bacterial pneumonia, 1 with acute bronchitis, 1 with chronic bronchitis, 1 with acute pharyngolaryngitis, 1 with tonsillitis and 1 with acute cystitis. The clinical response was good in 8 cases and fair in 1 of the 9 patients able to be evaluated, and the efficacy rate was 88.9%. In the bacteriological efficacy, S.aureus and α-Streptococcus were isolated from 2 patients with bacterial pneumonia, K.pneumoniae from 1 with acute bronchitis, S.aureus from 1 with chronic bronchitis, Streptococcus pyogenes from 1 with tonsillitis and E. coli from 1 with cystitis, and all isolated organisms were eradicated except S.aureus in bacterial pneumonia and unknown in tonsillitis. Subjective and objective side effects were observed eruption in a patient with tonsillitis, and blister with glossitis in a patient with acute cystitis.
From the above results, NM441 showed a wide antibacterial spectrum and good clinical response, and it was considered a useful drug for use in internal medical infections.

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We studied NM441, a new oral quinolone antimicrobial agent, and obtained the following results.
1) Serum and urinary levels of NM394 were determined after oral administration of NM441 (200mg) to 9 patients with renal dysfunction and 4 elderly patients (Ccr≥50ml/min). In the patients with severe renal impairment, serum concentration decreased more slowly than in those with slight and moderaterenal inpairment, and high serum levels lasted over a long period. Urinary excretion of NM394 diminished depending on the degree of renal function. In the elderly patients, serum concentration and urinary excretion did not differ greatly from those in the patients with slightly renal impairment.
2) Serum and sputum levels of NM394 were determined after oral administration of NM441 (300mg) to 2 patients with chronic respriratory infection. The peak level of NM394 in 1 patient was 1.86μg/ml in serum and 1.84μg/ml in aspirated sputum, and in the other patient was 0.78μg/ml in serum and 0.22μg/ml in expectorated sputum.
3) Clinical results: 25 patients were treated with NM441. The clinical response was good in 22 and poor in 3 cases with an efficacy of 88.0%. Laboratory tests revealed elevation of GOT and GPT in 1, elevation of GOT in 1, elevation of GPT in 2 and elevation of BUN in 2 cases. No side effects caused by the drug were observed.

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Fundamental and clinical studies on a new quinolone antibiotic, NM441, were performed, and the following results were obtained.
1) NM441 was orally administered to 1 patient with secondary infection of bronchiectasis at a dose of 200mg once after meal, and the serum and sputum concentrations of NM394 were measured. Themaximum serum concentration was 0.66μg/ml at 2 h after administration, and the maximum sputum concentration was 0.12μg/ml at 8-12 h after administration.
2) The number of evaluable patients was 35 of total 37 cases, the clinical efficacy was excellent in 8 cases, good in 25 and poor in 2, with an efficacy rate of 94.3%.
3) The clinical efficacy rates classified by diagnosis were 94.1%(16/17) in pneumonia, 90.9%(10/11) in secondary infection of bronchiectasis, 4/4 in secondary infection of old pulmonary tuberculosis, 1/1 in chronic bronchitis, 1/1 in secondary infection of pulmonary emphysema and 1/1 in secondary infection of pneumonoconiosis.
4) The clinical efficacy rates classified by absence or presence of underlying disease were 100%(23/23) in absence and 83.3%(10/12) in presence.
5) The clinical efficacy rates classified by severity were 100%(15/15) in mild and 90.0%(18/20) in moderate.
6) The clinical efficacy rates classified by dosage were 1/1 in 100mg×2, 23/24 (95.8%) in 200mg×2, 0/1 in 200mg×3 and 9/9 in 300mg×2.
7) In the bacteriological efficacy, the eradicated rate was 78.6%(11/14).
8) The observed rate of side effects was 8.1%(3/37), and that of abnormal laboratory findings was5.4%(2/37).
From above evaluation items, NM441 was considered a useful drug for respiratory tract infections.

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We performed bacteriological and clinical studies on NM441, a new quinolone derivative, in respiratory tract infections and obtained the following results.
1) The MICs of NM394 (the active form of NM441) against methicillin-sensitive Staphylococcus aureus and Streptococcus pneumoniae were inferior to those of ofloxacin (OFLX), ciprofloxacin (CPFX) and tosufloxacin (TFLX). Its activity against methicillin-resistant S. aureus was weak, similar to those of OFLX, CPFX and TFLX. The MICs against Klebsiella pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were almost equal to those of OFLX, CPFX and TFLX. The MIC₉₀ of Pseudomonas aeruginosa was 4μg/ml, which was superior to those of OFLX, CPFX and TFLX.
2) Ten patients with respiratory tract infections were treated with NM441. Clinical efficacy was good in 7, fair in 1, poor in 1 patient and unevaluable in 1. No adverse reactions were obtained in any of the patients. Slight elevation of BUN was observed in 1 patient and slight elevation of GOT and increase of eosinophile were observed in 1 patient.

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We studied on antimicrobial activity of NM394, the active form of NM441, newly-developed quinolone, and on clinical efficacy of NM441 in respiratory tract infection.
1) Antimicrobial activity
The MICs of NM394 against clinically isolated 378 strains of 24 species, were measured in inoculum size of 10⁶ CFU/ml and compared with those of ofloxacin (OFLX), ciprofloxacin (CPFX) and fleroxacin (FLRX). Against methicillin-sensitive Staphylococcus aureus antimicrobial activity of NM394 was equal to those of the other drugs, and as to methicillin-resistant S.aureus the activities of 4 drugs were weak. Against Streptococcus pyogenes and Streptococcus agalactiae NM394 showed strong activity, but against Streptococcus pneumoniae the activity of the drug was inferior to those of other drugs. Against Enterobacteriaceae NM394 and CPFX showed excellent activities and superior to those of OFLX and FLRX. Against Pseudomonas aeruginosa the activities of NM394 was superior to those of the other drugs. Against Vibrio spp., Aeromonas hydrophila, Haemophilus influenzae and Moraxella catarrhalis the drug showed strong activity.
2) Clinical efficacy and adverse reaction
Two patients with pneumonia, 2 with chronic bronchitis, 2 with infected pulmonary emphysema and 3 with acute bronchitis were treated with NM441 at a daily dose of 200-400mg for 7 to 14 days. Clinical responses were excellent in 2 patients, good in 6 and poor in 1. Two strains of S. pneumoniae, 1 of Haemophilus parahaemolyties and 1 of S. aureus isolated from 3 patients were eradicated after NM441 treatment. Eruption with abnormality of liver function was observed in 1 patient.

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We performed basic and clinical studies on NM441, a new pyridonecarboxylic acid, in respiratory infections, with the following results.
1) The MICs of NM441 for causative organisms were measured using the agar dilution method with an inoculum size of 10₆CFU/ml.
The MICs for 16 strains of Staphylococcus aureus were 0.2-12.5μg/ml; for 27 strains of Streptococcus pneumoniae, 0.78-25μg/ml; for 25 strains of Mollaxella catarrhalis, 0.05-0.2g/ml; for 18 strains of Haemophilus influenzae, 0.025-0.78μg/ml; and for 21 strains of Pseudomonas aeruginosa, 0.1-25μg/ml.
2) Clinical evaluation of NM441 in 6 patients with respiratory infections were excellent in 1, good in 3 and fair in 2.
The side effect observed in 1 case was headache. No abnormalities in laboratory values were observed.
These results suggest that NM441 is a useful oral antimicrobial agent in respiratory infections.

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We performed bacteriological and clinical studies on NM441, a new quinolone antibiotic, with the following results.
The antibacterial activities of NM394 against clinical isolates (10 species, 242 strains) were compared with those of ofloxacin (OFLX), ciprofloxacin (CPFX) and tosufloxacin (TFLX). The MIC₉₀s of NM394 against methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S.aureus (MRSA), Enterococcus faecalis, Klebsiella pneumoniae, Citrobacter freundii, Proteus vulgaris, Escherichia coli, Enterobacter cloacae, Enterobacter aerogenes, Proteus mirabilis and Pseudomonas aeruginosa were 1.56, >100, ≤50, ≤0.05, ≤0.05, ≤0.05, 0.10, 0.10, 0.10, 0.20 and 1.56μg/ml, respectively. The activities of NM394 against gram-positive bacteria were less potent than those of TFLX, but almost as potent as OFLX and CPFX. The activities against gram-negative bacteria were almost as potent as those of CPFX, and more potent than those of OFLX and TFLX. In particular, NM394 showed a high antibacterial activity against P. aeruginosa.
NM441 was administered to a total of 22 patients, 20 cases with respiratory tract infections and 2 urinary tract infections, at a daily dose of 200-400mg for 2-21days. Clinical response was excellent in 5 cases, good in 15 and fair in 2. Side effects were observed in a total of 3 cases (13.6%), insomnia in 1, nausea·vomiting in 1 and rash in 1. Abnormal laboratory findings were observed in a total of 3 cases (13.6%), elevations of S-GOT·S-GPT·γ-GTP, S-GOT and S-GOT·S-GPT each in 1 case.

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A new developed antimicrobial agent, NM441, was evaluated in vitro and in vivo. The results were asfollows:
1) Antimicrobial activity: Minimal inhibitory concentrations (MICs) against 503 clinical isolates of 16different species were determined, and compared with those of the other 4 kinds of drugs, norfloxacin (NFLX), ofloxacin (OFLX), ciprofloxacin (CPFX) and lomefloxacin (LFLX). NM441 showed excellentantimicobial activities against gram positive and negative bacteria.
2) NM394 concentrations in serum and sputum: A patient with diffuse panbronchiolitis and a patientwith bronchiectasis were given 200mg of NM441 orally. Another patient with bronchiectasis was given300mg of NM441 and 1g of S·M powder. The concentrations in serum were measured at intervals. Thepeak concentrations in serum were observed immediately after administration orally, and reached 0.9-1.3μg/ml after 2 hours. The peak sputum levels, 0.3-0.5μg/ml, were observed in about 4 hoursafter administration. These results suggest that NM394 can penetrate rapidly into the sputum. However, S·M powder inhibited absorption of NM441.
3) Clinical efficacy and adverse reaction: Twenty patients with respiratory or urinary tract infectionwere treated with NM441.
An overall efficacy were excellent in 6 cases, good in 10, poor in 2, and not evaluable in 2. Side effectwas not observed in any case. As the laboratory abnormal findings, elevation of GOT and GPT in one casewas observed. However, since these were mild increase, the safety of NM441 in clinical use was indicated.

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We compared the in vitro antimicrobial activity of NM394, a new quinolone antibiotic, with those ofother new quinolones, ofloxacin (OFLX), tosufloxacin, ciprofloxacin, sparfloxacin and fleroxacin. MIC₅₀sand MIC₈₀s of NM394 against respiratory pathogenic bacteria were 3.13μg/ml and 50μg/ml against Staphylococcus aureus (45 strains), 1.56μg/ml and 3.13μg/ml against Streptococcus pneumoniae(43 strains), 0.1μg/ml and 0.1μg/ml against Moraxella (Branhamella)catarrhalis(43 strains), 0.025μg/ml and 0.025μg/ml against HaemoPhilus influenzae(44 strains), and 0.39μg/ml and 1.56μg/ml against Pseudomonasaeruginosa(46 strains). The antibacterial activity of NM394 was superior to those of other drugs against P. aeruginosa, but that of NM394 was similar to that of OFLX against the other bacteria.
NM441, a prodrug of NM394, was administered to 3 patients with respiratory tract infections each ata dose of 100mg, 200mg or 300mg twice a day, and the serum and sputum concentrations of NM394 weremeasured. The maximal serum levels of NM394 were 0.14μg/ml, 1.25μg/ml and 1.65μg/ml, and themaximal sputum levels were 0.36μg/ml, 0.27μg/ml and 0.11μg/ml, respectively. Thus, the penetration ofNM441 into sputum was not dependent on the serum concentration.
NM441 was administered to 16 patients with respiratory tract infections, and its clinical efficacy wasinvestigated. The clinical efficacy rate was 87.5%. In bacteriological efficacy, which reflects the in vitro antibacterial activity and the sputum concentration, all of S.pneumoniae, H. influenzae and M. catarrhalis were eradicated, while the eradication rate of S. aureus and P. aeruginosa was 50%.
No side effect nor abnormal laboratory finding caused by NM441 was observed.
From these results, we conclude that NM441 is a useful antibiotic for the treatment of respiratory tractinfections.

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We examined NM441, a new developed new-quinolone antimicrobial, for its pharmacokinetics in theserum and sputum, and for its clinical efficacy in respiratory tract infections. The results were as follows.
1) Antimicrobial activity
The minimal inhibitory concentrations (MICs) of NM394, the active form of NM441, were measured for741 clinically isolated strains of 18 species of bacteria (including gram-positive cocci, Moraxella catarrhalis, gram-negative bacilli and Bacteroides fragilis), and compared with those of ofloxacin (OFLX), lomeflo-xacin (LFLX) and tosufloxacin (TFLX). NM394 showed lower activity than TFLX, but higher than LFLX.And it was equal to or more powerful than OFLX.
2) Serum and sputum levels
Serum and sputum concentrations of NM394 were studied in a patient with seconday bronchitis aftermultiple oral administration of 200mg of NM441 twice daily for 7 days. The maximum serum level was1.12μg/ml, and the maximum sputum level was 0.35μg/ml.
3) Clinical results
200mg of NM441 twice daily was given 3 patients with respiratory tract infections for 7 or 11 days. Clinical efficacy was as good in 2 cases and fair in 1 case. No subjective or objective side effects and noabnormalities in laboratory values were observed.

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We performed basic and clinical studies on a new quinolone antibiotic, NM441, and the following results were obtained.
1) Antimicrobial activity
The minimum inhibitory concentrations (MICs) of NM394, an active form of NM441, against a total of 362 clinical isolated strains of 13 species were measured and compared with those of other 4 drugs (ofloxacin, ciprofloxacin, tosufloxacin and sparfloxacin).
2) Concentrations in serum and sputum
NM441 was administered to 1 patient with pneumonia at a dose of 200mg once, and the serum and sputum concentrations of NM394 were measured by HPLC method. The maximum serum concentration was 0.61μg/ml at 2h and 4h after administration, and the maximum sputum concentration was 1.21μg/ml at 4-6h after administration. These results suggested the favorable penetration of NM441 into lungs.
3) Clinical study results
NM441 was administered to 16 patients with respiratory infections, and its clinical efficacy, bacteriological efficacy and side effects were investigated. Clinical response was excellent in 3 cases, good in 12 and poor in 1, and the efficacy rate was 93.8%, showing a favorable response. As for side effects and abnormal laboratory findings, eruption in 1 case, nausea in 1 and increase of eosinophil in 1 were observed. However, all of these cases improved immediately after termination of NM441 treatment, and the safety of NM441 was confirmed.

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A dose-finding study on NM441, a novel new quinolone antimicrobial agent, for the patients with chronic respiratory tract infections was conducted with comparison to ofloxacin (OFLX). The daily dose of each drug was 400mg of NM441 given in 2 divided dosage (Group L), 600mg of NM441 given in 2 divided dosage (Group H) and 600mg of OFLX given in 3 divided dosage (Group C).
The results obtained in this study were as follows.
1) Ninety one patients were enrolled in the study. Eighty two cases were evaluable for clinical efficacy. The clinical efficacy rates were 84.6% in Group L, 89.3% in Group H and 96.4% in Group C.
2) The bacterial eradication rates were 81.8% in Group L, 90.9% in Group H and 100% in Group C.
3) Side effects were seen in 3.6% of cases in Group L, 10.3% of cases in Group H and 0% of cases in Group C. Laboratory abnormal findings were observed in 16.7% of cases in Group L, 0% of cases in Group H and 14.8% of cases in Group C. Neither severe side effect nor laboratory abnormality was seen.
4) The usefulness rates were 81.5% in Group L, 82.8% in Group H and 96.4% in Group C.
In all evaluation items described above, there were no significant differences between the 3 groups.
The evidence indicates that a daily dosage of 600mg of NM441 would be considered an optimal clinical dosage for the treatment of the patients with chronic respiratory tract infections, including intractable cases.

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Fundamental and clinical studies of NM441, a new quinolone antimicrobial agent, were performed.
In the fundamental study, MICs of NM394, the active form of NM441, were examined against isolates obtained from patients with urinary tract infection and stored at our department and compared with those of ofloxacin, ciprofloxacin and tosufloxacin. Against gram-positive cocci (methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Staphylococcus epidermidis, Enterococcus faecalis and Enterococcus faecium), the MIC₉₀ of NM394 showed the highest values, 16μg/ml, against E. faecium. While, the MIC₉₀s of NM394 against gram-negative rods (Escherichia coli etc.) were 0.5μg/ml or less excluding 16μg/ml against Pseudomonas aeruginosa and 4μg/ml against Serratia marcescens.
In comparison with other drugs as the antibacterial activities against gram-positive cocci, the MIC₉₀ of NM394 was almost equal to those of the other drugs against MRSA and superior to those against E. faecium. In the activities against gram-negative rods, the MIC₉₀s of NM394 against S. marcescens and P. aeruginosa was superior to those of the other antimicrobial agents.
The clinical study was performed in the total of 26 patients, including 20 with acute uncomplicated cystitis (AUC) and 6 with chronic complicated cystitis (CCC). Efficacy evaluation was performed according to the criteria of Japanese UTI Committee, and 12 patients with AUC were determined to be eligible for the evaluation. The clinical efficacy rates were 100% in both patients treated with single administration and administration for 3 days. In the bacteriological efficacy, all 12 strains of causative organisms were eliminated. While, efficacy evaluation was performed according to the criteria of Japanese UTI Committee, and 5 patients with CCC were determined to be eligible for the evaluation. The evaluation at 5th day was excellent in 4, and the efficacy rates were 80%. In the bacteriological efficacy, all 8 strains of causative organisms were eliminated. However, E. faecalis and Candida tropicalis appeared after treatment in 1 patient.
Side effects were observed in 2 of 26 patients, mild headache and nausea, and skin rash in 1 patient each. Each symptom was disappeared by withdrawal.

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We fundamentally investigated antimicrobial activity of NM394 in urine medium and influence of NM394 on bactericidal activity of leukocytes in order to clarify NM441 in vivo effects against urinary tract infections (UTI). We also investigated clinical efficacy and safety of NM441 for UTI in order to clarify its usefulness for UTI.
1) Antimicrobial activity of NM394 in human urine: Antimicrobial activity of NM394 was reduced in the presence of high concentration of magnesium or low p H of urine. However, there was no influence of calcium concentration of urine on antimicrobial activity of NM394.
2) Influence of NM394 on superoxide generation by leukocytes: The superoxide generation of polymorphonuclear leukocytes (PMNs) was suppressed by NM394. The superoxide generation of monocyte was not influenced in the presence of 1μg/ml of NM394. It was significantly suppressed in the presence of 10μg/ml of NM394. It was significantly enhanced in the presence of 100μg/ml of NM394.
3) Clinical study of NM441: We orally administered 100mg of NM441 twice a day for 5-9 days to 4 patients with chronic complicated UTI. The clinical efficacy was evaluated as excellent in 1 case and poor in 3 cases. No side effects or no abnormal laboratory findings were caused by NM441.

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NM394 (the active form of NM441), a new quinolone antimicrobial agent, was evaluated in terms of its MIC values against clinical isolates and for clinical efficacy in patients with urinary tract infections (UTI). The MIC values for 147 strains consisting of 6 species isolated from UTI were compared against those of norfloxacin, ofloxacin, enoxacin, tosufloxacin (TFLX) and fleroxacin.
Against Staphylococcus aureus and Enterococcus faecalis, the antibacterial activities of NM394 were slight inferior to those of TFLX and superior to those of the other comparative drugs. Against Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Pseudomonas aeruginosa, the antibacterial activities of NM394 were superior to those of the other drugs tested.
The clinical efficacy of NM441 was evaluated for a total of 36 patients, 9 with acute uncomplicated cystitis (AUC), 27 with complicated UTI without indwelling catheter. Efficacy was judged according to the criteria of the Japanese UTI Committee. The clinical efficacy rate in the evaluable 7 cases with AUC was excellent. The clinical response in the evaluable 25 cases with complicated UTI was excellent in 12 and moderate in 9, the efficacy rate being 84.0%.
As a side effect of NM441, eruption was observed in one of the 36 cases. Abnormal laboratory findings were not observed in any of the 34 cases. We conclude that NM441 is a useful drug in the treatment of urinary tract infections.

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We investigated the bacteriological and clinical efficacy of NM441 in male gonococcal urethritis.
1) MIC range of NM394 against clinical isolates, 3 strains of penicillinase producing Neisseria gonorrhoeae (PPNG;β-lactamase producing strains) and 31 strains of non-penicillinase producing N. gonorrhoeae (non-PPNG;β-lactamase non-producing strains), was ≤0.003-0.2μg/ml. MIC₉₀s against non-PPNG and PPNG were 0.2 and 0.1μg/ml, respectively, and the values were higher than those of norfloxacin and fleroxacin and lower than those of sparfloxacin and levofloxacin.
2) NM441 was orally administered to 18 patients with gonococcal urethritis at 200mg twice a day for 3 days.
3) In the doctor's evaluation, the clinical response was excellent in 14 cases, good in 2 and unknown in 2 of 18 patients with gonococcal urethritis. Eleven patients were evaluable to the criteria of Japanese UTI Committee, and the overall clinical response was excellent in 8 cases, moderate in 2 and poor in 1, showing the efficacy rate 91%.
4) No side effects nor abnormal changes of laboratory findings were noticed.

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We performed basic and clinical studies of NM441, a new quinolone antibiotic, in chronic bacterial prostatitis, and the following results were obtained.
1. Basic study
1) Human prostatic tissue concentrations
Concentrations in the prostatic tissue (Mean) were 1.72, 1.20, 1.25, 1.29, 1.17, 0.52 and 0.38μg/g, and the serum concentrations (Mean) were 1.42, 0.40, 0.28, 0.42, 0.36, 0.19 and 0.06μg/ml at 1.5, 2, 2.5, 4, 6, 8 and 24h after 200mg of NM441 administration, respectively. The ratios of the concentrations of prostatic tissue and serum were 0.71 to 13.0.
2) Human prostatic fluid concentrations
Concentrations in the prostatic fluid were<0.01 to 0.44μg/ml at lh after 200mg of NM441 administration, and mean concentrations were 0.05, 0.02 and 0.14μg/ml at 1.5, 2 and 4h after administration, respectively. The serum concentrations (Mean) were 0.50, 0.73, 0.80 and 0.28μg/ml at 1, 1.5, 2, and 4h after administration, respectively. The ratios of the concentrations of prostatic fluid and serum were 0.02 to 1.62.
2. Clinical study
NM441 was orally administered to 22 patients with chronic bacterial prostatitis at a dose of 200mg twice a day for 10-22 days (Mean: 14.3 days). The clinical efficacy rate was 76.5% in 17 patients evaluable according to the criteria of the Japanese UTI Committee.
Side effects were observed in a total of 2 cases; stomach discomfort and heartburn in 1, and oral cavity discomfort in 1, but all were mild and the treatment was continued. An abnormal laboratory finding was observed eosinophilia in 1 case, but this case recovered at 8 days after the termination of administration.

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We studied the antimicrobial activity of NM441, a new fluoloquinolone antibiotic, and its clinical value in urinary tract infection (UTI).
1) The MICs of NM394, active form of NM441 and controlled antibiotics (norfloxacin, ofloxacin (OFLX) and ciprofloxacin) were measured using the plate dilution method against clinical isolates from urinary tract. The MIC₉₀ of NM394 against methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), Staphylococcus epidermidis and Enterococcus faecalis were 12.5, > 100, 12.5 and 25μg/ml respectively. These results were superior to the 3 controlled drugs with an exception of OFLX against MRSA. Those against Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens were 0.05, 12.5, 6.25, 6.25, 6.25μg/ml respectively. The MICs of NM394 against Pseudomonas aerukinosa ranged 0.1 to 50μg/ml. These results were also superior to the 3 controlled drugs.
2) Ten patients with complicated UTI were treated with 200mg of NM441 twice a day for 5 to 7 days. The therapeutic efficacy was evaluated by the criteria proposed by the Japanese UTI Committee. Of the 9 patients with complicated UTI, it was excellent in 4, moderate in 3 and poor in 2 patients.
Neither side effect nor laboratory adverse reaction was observed in any case.
Therefore, this study demonstrated NM441 to be an effective and safe antibiotic drug in the treatmentof UTI.

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NM441, a new quinolone derivative, was given to 40 patients with non-catheterized complicated urinary tract infections (UTI) to evaluate clinical efficacy and safety. To 14 patients NM441, at the daily dose of 200 or 400mg, was administered for 5-7 days, and to 26 patients for 14 days. According to the criteria proposed by the Japanese UTI committee, clinical efficacy was evaluated at 5-7 days on 9 patients, and at day 7 and day 14 on 17 patients. After 14-days treatment the rate of recurrence was assessed by bacterial counts in urine.
The results were as follows.
1) Overall clinical efficacy rate on 5-7-days treatment group was 100%(9/9). Bacteriologically, 14 of 15 strains (93.3%) were eradicated.
2) Overall clinical efficacy rates on 14-days treatment group were 76.5%(13/17) at day 7 and day 14. Bacteriologically, 21 of 25 strains (84.0%) were eradicated at day 7 and day 14. Final efficacy rates and eradication rates were the same as at day 7 and as at day 14.
3) Eight patients were assessable for recurrence of infections at 1-2 weeks after treatment, relapse was observed on 1 patient. Five patients were assessable for recurrence of infections at 3-6 weeks after treatment, re-infection and relapse was each observed in 1 patient.
4) Side effect was noted in 1 patient with angular stomatitis, but the symptom was mild and transient. No abnormal laboratory findings were observed.

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We studied the antibacterial activity and clinical efficacy of NM441, a new oral quinolone, which is the prodrug of the biologically active NM394.
1) Antibacterial activity: We measured the MICs of NM394 against 200 clinical isolates from urinary tract infections (UTI), and compared them with those of ofloxacin (OFLX), ciprofloxacin (CPFX), norfloxacin (NFLX), sparfloxacin (SPFX), lomefloxacin (LFLX) and tosufloxacin (TFLX).
The antibacterial activities of NM394 against gram-positive bacteria were a little inferior to those of SPFX, LFLX or TFLX, but were comparable to those of OFLX or CPFX. On the other hand, against gramnegative bacteria, in general, antibacterial activities of NM394 were superior to those of other new quinolones.
2) Clinical efficacy: According to the criteria of the Japanese UTI Committee, the overall clinical efficacy rate was 100%(9/9) for uncomplicated UTI and was 88.9%(24/27) for chronic complicated UTI.
Bacteriologically, 25 of 29 strains (86.2%) were eradicated for chronic complicated UTI.
3) Side effect: Nausea was observed in 1 patient (2.2%), and an abnormal laboratory finding was observed in 1 patient (2.2%), that showed transient eosinophilia.

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