We evaluated the in vitro antibacterial activity of garenoxacin mesilate hydrate (GRNX). Results are summarized as follows:
1. GRNX showed a broad spectrum of potent activity against Gram-positive and Gram-negative bacteria in both aerobic and anaerobic bacteria, Chlamydia spp., Mycoplasma pneumoniae and Legionella spp.
2. GRNX showed potent antibacterial activity against clinical isolates of Gram-positive bacteria. The MIC₉₀s of GRNX against methicillin-susceptible Staphylococcus aureus (MSSA) and Streptococcus spp., including penicillin-resistant Streptococcus pneumoniae (PRSP) were 0.05μg/mL to 0.1μg/mL and were 1/2 to 1/32 than that of levofloxacin (LVFX), gatifloxacin (GFLX), moxifloxacin (MFLX) ciprofloxacin (CPFX) and tosufloxacin (TFLX).
3. In Gram-negative bacteria, the MIC₉₀ of GRNX against Haemophilus influenzae, Moraxella catarrhalis and Klebsiella pneumoniae, major pathogens of respiratory tract infection, were 0.025 to 1.56μg/mL, and were the same as that of other quinolones tested.
4. The MIC of GRNX against Chlamydophila pneumoniae and MIC₉₀ of GRNX against M. pneumoniae were 0.002μg/mL to 0.008μg/mL and 0.0313μg/mL, respectively, and were lowest among quinolones tested. The MIC₉₀ of GRNX against Legionella pneumophila was the same as that of GFLX and more potent than that of other quinolones tested.
5. The in vitro antibacterial activity of GRNX was not influenced by the type of medium, medium pH, addition of human serum, or inoculum size.
6. The action of GRNX was bactericidal. The mutant prevention concentrations (MPCs) of GRNX against S. aureus and S. pneumoniae including quinolone-resistant strains were less than 1μg/mL, and were lower than those of LVFX and GFLX.
7. The inhibitory effect of GRNX against DNA gyrase and topoisomerase IV of S. aureus and S. pneumoniae was more potent than that of LVFX and GFLX.
8. In an in vitro pharmacokinetic model simulating serum concentration of GRNX following 400mg single oral administration, GRNX showed a potent bactericidal activity against quinolone-resistant S. pneumoniae.

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In vivo antibacterial activity of garenoxacin (garenoxacin mesilate hydrate: GRNX) on various experimental infections was evaluated.
1. In systemic infection caused by methicillin-resistant Staphylococcus aureus (MRSA) in mice, the 50% effective dose (ED₅₀) of GRNX was 0.00593mg/mouse, and was lower than that of levofloxacin (LVFX) and gatifloxacin (GFLX). Against penicillin-resistant Streptococcus pneumoniae (PRSP), the ED₅₀ of GRNX was 0.555mg/mouse, lower than that of LVFX and similar to that of GFLX. The efficacy of GRNX on both Escherichia coli and Pseudomonas aeruginosa infections was similar to that of LVFX and GFLX.
2. In pneumonia caused by PRSP in mice, the viable cell counts in lung after treatment with GRNX was<2.68 Log of CFU/lung, less than that with LVFX and GFLX.
3. In pneumonia caused by Mycoplasma pneumoniae in hamsters, GRNX showed better efficacy than LVFX and clarithromycin (CAM).
4. In pneumonia caused by Chlamydophila pneumoniae in mice, the ED₅₀ of GRNX was 0.0286 mg/mouse, lower than that of LVFX and azithromycin (AZM).
5. In pneumonia caused by Legionella pneumophila in guinea pigs, the viable cell counts after treatment of GRNX was 2.84 Log of CFU/lung, lower than that of ciprofloxacin (CPFX) and CAM, and similar to that of rifampicin.

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Single oral and intravenous toxicity studies of garenoxacin mesilate hydrate (GRNX) were conducted in mice, rats, and dogs.
No mice, rats, or dogs died at the maximum dose of 2, 000 mg/kg in oral administration. The lethal dose was exceeded 2, 000 mg/kg in all species. Soft feces was observed at 2, 000 mg/kg in rats. In dogs, decreased locomotor activity, vomiting, salivation, hypothermia and increased pulse rate were seen at 1, 000 mg/kg or higher, and body weight and food consumption decreased transiently at 2, 000 mg/kg.
Lethal doses in single intravenous dose studies were 200-250 mg/kg in male and 250 mg/kg in female mice; 250-300 mg/kg in both male and female rats; and 200-300 mg/kg in male dogs. In mice and rats, decreased locomotor activity, lateral/prone position, staggering gait, crawling, decreased respiration, clonic convulsion, mydriasis, straub tail, and/or salivation were observed at 150 mg/kg or higher. Decreased body weight and suppression of body weight gain were transiently observed at 150 mg/kg or higher in mice and 200 mg/kg or higher in rats. In dogs, at 200 mg/kg or higher, decreased locomotor activity, salivation, flushing, vomiting, hypothermia, increased pulse rate, and decreased body weight and food consumption were observed, with edema of the head and tonic convulsions noted at 300 mg/kg. In dead rats and dogs, congestion was observed in the lung, liver, stomach, and small intestine.
Results in single-dose toxicity studies of GRNX in mice, rats, and dogs indicate that toxic changes were similar to those of fluoroquinolone antibacterial agents, there was no specific toxicity to GRNX.

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Garenoxacin mesilate hydrate (GRNX) was administered to male (50, 100, 200 and 400 mg/kg) and female (100, 200, 400 and 800 mg/kg) SD rats orally for 3 months, and toxicity was assessed. Reversibility of toxic changes was also assessed in males receiving 200 and 400 mg/kg, and females receiving 400 and 800 mg/kg following 1-month withdrawal. In males, deposition of lipid droplets in hepatocytes was seen at doses of 100mg/kg and above; suppression of body weight gain, an increase in alkaline phosphatase, and a decrease in heart weight were seen at doses of 200 mg/kg and above; and decreases in triglyceride and salivary glands weight were seen at dose of 400 mg/kg. In females, an increase in alkaline phosphatase, a decrease in salivary glands weight, and lesions in the articular cartilage were seen at doses of 400 mg/kg and above; and decreases in triglyceride and heart weight, and deposition of lipid droplets in hepatocytes were seen at dose of 800 mg/kg. At the end of recovery, osteochondrosis in the articular cartilage was seen in males receiving 400mg/kg and females receiving 800 mg/kg. As other changes, changes (soft feces and dilatation in cecal lumen, etc.) attributed to change in intestinal bacterial flora due to the antibacterial activity of GRNX were seen in each group.
From the above, no observable adverse effect level was estimated at 50 mg/kg for males and 200 mg/kg for females. In toxicokinetics, a sex difference was seen in plasma concentration, and AUG_0-∞ in females was about one-fourth to one-third of that in males.
All of these changes were also seen in repeated dose toxicity studies of fluoroquinolone antimicrobial agents, and no peculiar changes in GRNX were seen.

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Garenoxacin (mesilate hydrate, GRNX) was administered by oral gavage to male and female cynomolgus monkeys at doses of 10, 30, and 100mg/kg once daily for 3 months and toxicity assessed. Reversibility of toxic changes was also assessed in animals receiving 30 and 100mg/kg following 3-month withdrawal. Animals receiving 100mg/kg showed vomiting and salivation during the dosing period; these clinical signs were seen approximately just after dosing and disappeared with time. In histopathology, stomachs of animals receiving 100mg/kg showed atrophy of fundic glands at the termination of the dosing period; this change improved by withdrawal. Abnormalities attributable to GRNX at each dose were not observed in body weight changes, food consumption, ophthalmology, electrocardiography, auditory sense, urinalysis, hematology, or blood chemistry. In the present study, no observed adverse effect level was established at 30mg/kg, and systemic exposure of GRNX at this dose level was as follows: Cmax was 11.2-16.9μg/mL, and AUC was 88.6-159μg·h/mL. Reddish-purple discoloration of several organs and tissues including oral mucosa, and blackish brown discoloration of thyroids were observed in animals receiving 30mg/kg and above. However, organs and tissues with discoloration did not have histological abnormalities related to the gross finding, and serum levels of thyroid hormones (triiodothyronine (T3), thyroxine (T4), free T3, and free T4) were not affected. Reversibility of discoloration was shown by withdrawal.

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A bacterial reverse mutation test, a gene mutation test in mammalian cultured cells, a chromosome aberration test in mammalian cultured cells, a micronucleus test in mice, and an in vivo unscheduled DNA synthesis test in rat hepatocytes were conducted to investigate the genotoxicity of garenoxacin mesilate hydrate (GRNX).
1. In the bacterial reverse mutation test, GRNX did not show mutagenic activity against tester strains (Salmonella typhimurium TA98, TA 100, TA 1535, TA 1537, and Escherichia coli WP2uvrA) in the absence and presence of metabolic activation (S9 mix).
2. In the gene mutation test with cultured mammalian cells (V 79 cells), no increase in 6-thioguanineresistant mutant colonies was observed in the absence and presence of the S9 mix.
3. In the chromosomal aberration test with cultured mammalian cells (CHL/IU cells), increases in the frequency of cells with chromosomal aberration were observed in the absence and presence of the S9 mix.
4. In the micronucleus test in mice, no increase was observed in the frequency of micronuclei.
5. In the in vivo unscheduled DNA synthesis test in rat hepatocytes, no increase of the number was observed with net nuclear grain and repair cells.
These results indicated that GRNX showed mutagenic activity against cultured mammalian cells based on its topoisomerase inhibitory activity, but not in the mice micronucleus test or other in vitro and in vivo studies. The GRNX is thus not considered to show the mutagenic activity in vivo.

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Reproductive and developmental toxicity studies of garenoxacin mesilate hydrate (GRNX) were conducted in Sprague-Dawley rats and New Zealand White rabbits.
In the oral study of fertility and early embryonic development to implantation in rats, suppressed body weight gain and decreased food consumption in males in the 100 and 400mg/kg groups, and suppressed body weight gain in females in the 1, 000mg/kg group were noted. No effects of GRNX were noted in reproductive ability, sperm examination, estrous cycle, or intrauterine condition on Day 15 of gestation.
In the oral study of pre-and postnatal development, including maternal function in rats, suppressed body weight gain and decreased food consumption were noted during gestation period in dams in the 250 and 1, 000 mg/kg groups. No effects of GRNX were noted in reproductive ability of dams, which were indicated by maintenance of pregnancy, delivery or nursing. In offspring, no effects of GRNX were noted in viability, body weight changes, general sign, postnatal development, reflex response, open field performance, learning ability, reproductive ability, or intrauterine condition on Day 20 of gestation.
In the oral study of embryo-fetal development in rats, suppressed body weight gain and decreased food consumption were noted in dams in the 1, 000mg/kg group. No effects of GRNX were noted in reproductive ability of dams, which were indicated by maintenance of pregnancy or findings of caesarean section at term. In fetuses, no effects of GRNX were noted in the number of live, dead and resorbed fetuses, body weights, sex ratio, or external, visceral and skeletal examination. GRNX was concluded to be not teratogenic in rats.
In the intravenous study of embryo-fetal development in rabbits, suppressed body weight gain and decreased food consumption were noted in dams in the 6.25, 12.5 and 25mg/kg groups, with abortion occurring for 1 to 3 dams. In the 12.5mg/kg group, death after abortion was observed for 1 dam. In fetuses, decreased body weight of live fetuses and increased incidence with thymic remnant in the neck were observed. These changes were considered to be an effect of delayed growth of fetuses due to the lower body weight of dams, and it could therefore be concluded that GRNX was not teratogenic in rabbits.

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The phototoxicity of Garenoxacin mesilate hydrate (GRNX) in guinea pigs was studied. In this study, the phototoxic potential of GRNX was compared to that of ciprofloxacin hydrochloride (CPFX) and levofloxacin (LVFX) as comparative articles.
Animals were administered a single dose intravenously with each article at the dose level of 100mg/kg as free base, and irradiated with ultraviolet A (UVA) of about 10 J/cm² for about 30 minutes starting at 10 minutes after administration. The skin reactions of these animals were observed macroscopically at 24 and 48 hours after irradiation. A control group was administered physiological saline.
GRNX showed no skin reaction after 24 and 48 hours. CPFX showed moderate skin reaction in all animals both after 24 and 48 hours. LVFX showed a slight skin reaction in one of six animals after 24 hours, but the skin reaction disappeared after 48 hours.
Plasma concentration of GRNX during irradiation (10 to 40 minutes after administration) with UVA was comparable to that of LVFX, and was higher than that of CPFX.
As mentioned above, we consider that the phototoxic potential of GRNX is weaker than that of CPFX and LVFX.

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The pharmacokinetics of a novel des-fluoro (6)-quinolone antibacterial agent, garenoxacin mesilate hydrate (GRNX), was investigated using several laboratory animal species. GRNX was rapidly absorbed and widely distributed into most tissues/organs except the cerebrum and spinal cord. Radioactivity was completely excreted from the body after the administration of [¹⁴C] GRNX in rats and monkeys, suggesting low persistence of GRNX. The linearity of systemic exposure on laboratory animal species was suggested among the dose range tested in this study (rats: 2 to 25mg/kg, dogs: 8 to 75mg/kg, and monkeys: 25 to 100mg/kg). The in vitro serum protein binding of GRNX was consistent in GRNX concentrations tested on mice, rats, dogs, monkeys, and humans (mice: 66.7 to 71.9%, rats: 86.5 to 89.0%, dogs: 64.5 to 67.6%, monkeys: 71.2 to 74.5%, and humans: 78.3 to 84.0%). The urinary recovery of GRNX in rats decreased with increasing dose. However, that in dogs was consistent at each dose; species difference was observed in the urinary excretion of GRNX. Systemic exposure of GRNX in female rats was lower than that in male rats (about 33% of AUC_0-∞in male), the gender difference was observed. No gender difference was observed in biliary and urinary excretion of radioactivity. One of the reasons for the gender difference in systemic exposure of GRNX is GRNX metabolism.

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To assess the possibility of pharmacokinetic drug-drug interactions of garenoxacin mesilate hydrate (GRNX), we investigated the metabolism of GRNX in human liver microsomes, the induction effect of GRNX on cytochrome P450 (CYP) 1A2 and CYP3A4 activity in primary cultured human hepatocytes, and the inhibition effect of GRNX on the metabolic activity of probe substrates for CYP isoforms in human liver microsomes. GRNX was hardly metabolized by human liver microsomes in the presence or absence of NADPH, showing that CYPs are unlikely to be involved in the metabolism of GRNX. GRNX did not exhibit the induction effect on CYP1A2 and CYP3A4 activity at up to 100 μmol/L, which was approximately 17-fold higher than the unbound GRNX concentration in plasma (approximately 6 μmol/L, calculated from the C_max at 400 mg repeated oral dose in humans). GRNX had little inhibition effect on the CYP1A2, CYP 2 A 6, CYP 2 C 9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 activity, and the 50% inhibition concentration for these CYP isoforms exceeded 1, 000 μmol/L. In conclusion, GRNX is unlikely to cause CYP-mediated drug-drug interactions in humans when it is administered concomitantly with other drugs.

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Pharmacokinetic profiles, safety, and food effect of oral garenoxacin mesilate hydrate (GRNX), a novel des-F (6)-quinolone, were evaluated in studies with healthy Japanese adult subjects. The intrinsic ethnic factor of GRNX was investigated by reviewing comparison of pharmacokinetic parameters by Japanese with results of oversea studies.
1. Pharmacokinetics: In the single-dose study, linearity was shown between pharmacokinetic parameters (Cmax and AUC) and the GRNX dose. In the multiple-dose study, pharmacokinetic parameters come up to steady-state after dosing for 7 days, and accumulation was not observed. Cmax and AUC on day 7 were 11.06 μg/mL and 110.9μg·h/mL.
2. Safety: No serious adverse events were observed in studies. GRNX was shown to be safe and well tolerated up to 600 mg single dose and 400mg QD multiple-dose for 14 days. No relationship was noted between the ratio of adverse events and dosage or plasma concentration.
3. Effect of meals: The effect on pharmacokinetic parameters by fed or fasted administration was investigated at oral 400mg dose. The fed/fasted ratio of geometric mean of Cmax and AUC were 0.876 and 0.925. The 90% confidential intervals for the ratios of the geometric mean of Cmax and AUC between fed and fasted were completely contained within the ranges specifying the absence of a food effect. The effect of meals was not found with GRNX.
4. Investigation of the intrinsic ethnic factor: Pharmacokinetic profiles of plasma concentration, metabolites, penetration to saliva, and ratio of protein-binding were investigated by comparing those with oversea studies. Pharmacokinetic profiles in Japanese were similar to results of oversea studies, and no intrinsic ethnic factor affected pharmacokinetic parameters of GRNX.

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The efficacy and safety of garenoxacin mesilate hydrate (GRNX), a des-F (6)-quinolone antibiotic, with 200 mg and 400mg administered once daily were evaluated in patients with respiratory tract infections. Plasma concentrations of garenoxacin were determined preliminarily.
1. Clinical assessment: The efficacy rates were 96.0%(24/25) in 200mg group and 87.5%(21/24) in 400 mg group at the end of treatment. The efficacy rates at the 7th day of post-treatment were 100%(19/19) in 200mg group and 94.7%(18/19) in 400mg group.
2. Bacteriological efficacy: The eradication rates were 100%(16/16) in 200mg group and 70.0%(7/10) in 400mg group at the end of treatment. The eradication rates at the 7th day of post-treatment were 100%(11/11) in 200mg group and 6/8 in 400mg group.
3. Safety: The incidence of drug-related adverse events was 9.7%(3/31) in 200mg group and 6.5%(2/31) in 400mg group. The incidence of drug-related laboratory abnormality was 26.7%(8/30) in 200mg group and 19.4%(6/31) in 400mg group.
4. Plasma concentration: The trough concentration of garenoxacin was 0.89±0.42μg/mL in 200mg group and 1.71±0.46μg/mL in 400mg group.
Results indicate that a 400mg daily dose of GRNX gives a favorable prognosis in treatment for patients with respiratory tract infections.

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The clinical efficacy and safety of garenoxacin mesilate hydrate (GRNX), a novel des-fluoro quinolone, and levofloxacin (LVFX) for bacterial pneumonia were investigated double blind. Clinical efficacy was observed at the end day of treatment, and comparing the results of the 7th day after treatment completion in European and South American studies, patients were treated with either GRNX 400 mg once daily (GRNX group) or LVFX 100 mg three times daily (LVFX group) for 10 days.
The efficacy rates at the end day of treatment were 99.1%(111/112) in the GRNXgroup and 94.9%(82/87) in the LVFX group. The noninferiority of GRNX against LVFX was demonstrated. Theefficacy rates at the 7th day after treatment completion were 94.9%(94/99) in the GRNX group and 92.8%(77/83) in the LVFX group. Bacteriological efficacy was 100% in both the GRNX group (59/59) and the LVFX group (40/40). The bacteriological eradication rates at the 7th day after treatment completion were100%(50/50) in the GRNX group and 86.8%(33/38) in the LVFX group. The incidence of drug-induced adverseevents, including laboratory abnormalities was 35.6%(48/135) in the GRNX group and 27.1%(32/118) in the LVFX group, indicating no significant difference between groups. The sort and grade of adverse events were also similar between groups, and no strange event was observed.
The efficacy rate of GRNX at the 7th day after treatment completion was 89.9%(89/99) in European and South American studies. The clinical efficacy and safety which were observed in our study were similar to those of overseas results.
Summarizing this study, GRNX, a 400 mg oral dose once daily for 10 days, shouldbe clinically a very useful medication in the treatment of bacterial pneumonia.

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The efficacy and safety of garenoxacin mesilate hydrate (GRNX), new oral des-fluoroquinolone antimicrobial, were investigated in patients with secondary infection occurred on chronic respiratory disorders. Patients were treated with GRNX 400 mg once daily for 10 days. Plasma concentration of GRNX in each patient was determined and the obtained clinical results were analysed based on pharmacokinetics (PK) and pharmacokinetics/pharmacodynamics (PK/PD) parameters.
Clinical efficacy rates were 87.8%(108/123) at the end of treatment and 83.7%(103/123) at the 7th day of post-treatment. Bacteriological eradication rates were 89.6%(60/67) and 85.1 %(57/67) at the above time points. Eradication rates of causative organisms were 100%(13/13) in Streptococcus pneumoniae, 7/8 in Staphylococcus aureus, 100%(28/28) in Haemophilus influenzae and 8/8 in Moraxella (Branhamella) catarrhalis at the end of treatment. All penicillin-resistant S. pneumoniae (PRSP) including penicillin-intermediate resistant S. pneumoniae (PISP) were eradicated.
Drug-related adverse events were observed in 19 patients (26 events), the incidence rate was 14.0%(19/136). Gastrointestinal disorders including 4 cases of diarrhea (2.9%), 3 of loose stool (2.2%) and 3 of vomiting (22%) were frequently observed. Laboratory abnormalities were observed in 26 patients (19.3%). Frequent abnormalities were 14 cases of AST elevation (10.4%), 13 of ALT elevation (9.6%) and 5 of serum amylase elevation (3.8%). No relationship was observed between PK parameters (AUC_0-24 and Cmax) and incidence of adverse events.
90.9% of patient in this study exceeded the target value of fAUC_0-24/MIC>50. Clinical efficacy at the 7th day of post-treatment was 91.7%(55/60) in those cases whose target value was more than 50, but it was only 3/6 in those whose target value was less than 50. Similar results were obtained in studies in US and EU.
From aboves, it indicates that GRNX is a beneficial antimicrobial agent for secondary infection of chronic respiratory diseases.

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The penetration into sputum of garenoxacin mesilate hydrate (GRNX), a new oral des-fluoroquinolone antibiotic, was evaluated in five patients with secondary infection to chronic respiratory disease. The efficacy and safety of GRNX were evaluated.
Concentrations of GRNX in sputum and plasma were measured during 400 mg once a day treatment for 10 days. The concentration reached maximum after 3-5 hours of administration, and the concentration values (average±SD) of GRNX in sputum after 3 hours and after 24 hours were 3.50±1.17μg/g and 0.784±0.199 μ g/g, respectively.
The trough concentration of GRNX in sputum indicated over MIC₉₀ of major causative organisms of respiratory tract infection; i.e., quinolone-susceptive Staphylococcus aureus: 0.025 μg/mL, Streptococcus pneumoniae: 0.05 μ g/mL, Haemophilus influenzae: 0.0125 μg/mL and Moraxella catarrhalis: 0.10 μg/mL. For the three cured patients in this study, whose causative organisms were eradicated, the concentration of GRNX in sputum after 24 hours of administration was greater than MIC of pathogens (Streptococcus constellatus, Pseudomonas aeruginosa and H. influenzae). No serious or significant adverse events were observed.
The above results suggest that GRNX shows good penetration into sputum and GRNX treatment is useful for patients with secondary infection to chronic respiratory disease.

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The clinical efficacy and safety of garenoxacin (GRNX), a novel des-fluoroquinolone, were observed in patients with respiratory tract infection including community-acquired pnuemonia and acute bronchitis caused by Mycoplasma pneumoniae, Chlamydia pneumoniae or Streptococcus pneumoniae, community organisms. All patients were treated with 400 mg once daily dose of GRNX for 7-10 days.
1. Clinical efficacy: The efficacy rate at the end day of treatment was 98.9%(88/89) in all cases of community-acquired pnuemonia, including pneumonia with M. pneumoniae 100%(20/20), with C. pneumoniae 92.3%(12/13) and with common bacterial organisms 100%(56/56). The efficacy rate for acute bronchitis was observed in 100%(13/13), including 12 cases with bacteria and 1 case with C. pneumoniae.
2. Bacteriological efficacy: The eradication rate at the end day of treatment was 81.8%(27/33) in all cases of community-acquired pnuemonia, including pneumonia with M. pneumoniae 6/6 and with common bacterial organisms 95.5%(21/22). The eradication rate for acute bronchitis was observed in 5/5.
Bacteriological response with 5 cases of mixed infection caused by bacteria, M. pneumoniae and C. pneumoniae was judged as partial eradication.
3. Safety: Adverse reactions involving 233 were observed in 93 cases of 144 cases (64.6%). Some 103 events of the side effects and drug induced laboratory abnormalities were observed in 55 out of 144 cases (382%). Abnormalities seen most frequently were increases in ALT and AST, but the incidence was 10.5%(15/143) in the former and 5.6%(8/143) in the latter.
From above findings of GRNX, a 400 mg oral dose once daily treatment may be useful for patients with respiratory tract infections including mycoplasma pneumonia, chlamydia pneumonia and acute bronchitis.

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The efficacy and safety of garenoxacin mesilate hydrate (GRNX), a novel oral des-fluoroquinolone, were evaluated in patients with respiratory tract infection caused by penicillin-intermediate resistant S.pneumoniae (PISP) and penicillin-resistant S. pneumoniae (PRSP).
1. Clinical efficacy: The efficacy rates at the end of treatment in patients caused by PISP, PRSP, and penicillin-susceptible S. pneumoniae (PSSP) pathogens were 8/9, 93.8%(15/16) and 100%(22/22). The efficacy rate in patients with resistance-unknown S. pneumoniae was 4/4, and the total efficacy rate was 96.1%(49/51). The efficacy rates at 3 days after treatment in total, PRSP, PISP, PSSP and resistance-unknown strains were 84.3%(43/51), 8/9, 75.0%(12/16) and 4/4.
2. Bacteriological efficacy: The eradication rates at 3 days after treatment or at the end of treatment in total, PRSP, PISP, PSSP and resistance-unknown strains were 100%(50/50), 9/9, 100%(16/16), 100%(21/21) and 4/4.
3. Safety: Incidence of adverse events and laboratory abnormalities were 8.1%(8/99) and 30.3%(30/99). No strange event was observed. No clinically relevant electrocardiogram abnormalities mere noted.
Results suggest that 400 mg daily treatment of GRNX administered is useful for patients with respiratory tract infection including patients caused by penicillin-resistant S. pneumoniae.

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Pharmacokinetic and clinical studies on garenoxacin mesilate hydrate (GRNX), a new synthetic des-F (6)-quinolone antimicrobial agent, 400 mg once daily were observed in otorhinolaryngological infections.
1. Penetration into tissues: The concentration of GRNX were 6.01 μg/g in maxillary sinus mucosa, 5.89μg/g in middle ear mucosa, and 9.44 μg/g in tonsil at 2.5-3.5 hours after GRNX 400 mg p.o. The ratio against plasma concentration was 1.03-1.61.
2. Clinical efficacy: Clinical efficacy rates were 92.0%(23/25) in paranasal sinusitis, 95.2%(20/21) in acute tonsillitis, 85.0%(17/20) in acute pharyngolaryngitis and 872%(41/47) in acute and otitis media. Overall clinical efficacy rate was 89.4%(101/113).
3. Bacteriological response: Bacteriological eradication rates were 94.1%(32/34) in S. aureus, 100%(20/20) in S. pneumoniae, 100%(20/20) in H. influenzae, 100%(14/14) in M.(B.) catarrhalis, 2/3 in MRSA, 5/5 in PRSP, 3/3 in PISP, 100%(14/14) in BLNAR. Overall bacteriological eradication rate was 97.8%(131/134).
4. Safety: Side effects were observed in 17.4%(21/121), but no serious or clinically significant event was noted.
Results, indicate that GRNX is a very useful medication for the treatment of otorhinolaryngological infections.

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The effect on the plasma concentration of theophylline when garenoxacin mesilate hydrate (GRNX), a new quinolone antibacterial agent, was administered concomitantly was evaluated in 9 healthy male adult volunteers. Initially 400mg of theophylline at a daily dose was given orally for 4 days prior to GRNX administration. The plasma concentration of theophylline was determined on day 4 and used as the control level. From day 5, 400mg of GRNX was given orally once daily in the morning for 7 days with concomitant administration of theophylline at the same dose as above.
The geometric mean Cmax and AUC values of theophylline on day 11 (the 7th day after GRNX administration started) were 1.18 and 1.19 times of the control values. The 90% confidential interval for the ratios of the geometric mean of Cmax was 1.02-1.37 and AUC was 1.03-1.37. On day 8 (the 4th day after GRNX administration started), these parameters were 1.18 and 1.19 times of the control values indicating same values as the day 11. No significant difference was noted in plasma level and/or pharmacokinetic parameters of GRNX between day 8 and day 11.
After GRNX administration started, seven adverse events occurred in five subjects. Side effects were observed in two subjects. Events were diarrhea (2 subjects, 2 events) and abdomen pain (1 subject, 1 event). All events were judged mild and both subjects recovered without treatment.
From the above results, GRNX was considered to increase the plasma level of theophylline by approximately 20% when administered concomitantly. Adjustment of the dosage of GRNX seems unnecessary, but careful monitoring is recommended when high-dose theophylline is administered, e.g., intravenously.

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The effect of garenoxacin mesilate hydrate (GRNX), a novel quinolone antimicrobial, on QT interval was investigated. Electrocardiogram data from 66 healthy volunteers was analyzed in the clinical pharmacology study, and 504 patients who received 400mg/dose/day in phase III clinical trials on infected patients.
At around Tmax (two hours after administration) of the single dose study, in the subject group who received 600mg administration, the mean QTc was 365.8 ± 26.9msec, and the mean ΔQTc was-1.8±25.4 msec, and did not have the tendency to prolong QTc.
The mean d QTc of phase III clinical studies were-10.5 ± 27.0msec at three days after administration, and-9.0 ± 27.8msec at nine days after administration, and there was no tendency of prolongation.
In an analysis by category, there were three of 504 patients in phase III clinical trials who had QTc exceeding 450msec (470msec: females) and ΔQTc exceeded 60 msec, but these QTc and d QTc were due to a clinical background.
In an investigation on the relationship between ΔQTc and the plasma concentration of the drug, no correlation was observed. No significant changes in the electrocardiogram wave pattern by this drug or adverse events related to QTc prolongation were observed. No correlation was observed between QTc or ΔQTc, and age or weight distribution of patients.
From these observations, we conclude that GRNX has no appreciable effect on QTc intervals.

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Subjects with infection caused by Streptococcus pneumoniae were chosen from eight studies of garenoxacin mesilate hydrate (GRNX), a novel oral des-fluoroquinolone, for treatment against respiratory tract infection and otorhinolaryngological infection. Susceptibility to antimicrobial agents, gene analysis of penicillin binding protein (PBP) mutation and macrolide-resistant genes, and clinical response against multidrug-resistant S. pneumoniae were evaluated for subjects. In 130 S. pneumoniae isolates as causative organisms from subjects treated by GRNX, the incidence of penicillin-resistant S. pneumoniae (PRSP) and penicillin-intermediate resistant S. pneumoniae (PISP) were 20.8%(27/130) and 26.2%(34/130). 106 S. pneumoniae susceptibility tests were redone to examine the degree of resistance to antimicrobial agents. MIC90 values of antimicrobial agents against 106 S. pneumoniae were 0.125 it g/mL for GRNX, 2 μg/mL for levofloxacin, 0.5 μg/mL for gatifloxacin, 0.25 μg/mL for moxifloxacin, 8 μg/mL for cefuroxime, > 128 μg/mL for erythromycin, > 128μg/mL for azithromycin, 0.25 μg/mL for telithromycin, 64 μg/mL for tetracycline and 2 μg/mL for sulfamethoxazoletrimethoprim (ST). Among these antimicrobial agents, GRNX showed the strongest activity. In 106 S. pneumoniae isolates, 2.8%(3/106) were quinolone-resistant, 44.3%(47/106) were/3-lactam-resistant, 79.2%(84/106) were macrolide-resistant, 80.2%(85/106) were tetracycline-resistant, 9.4%(10/106) were ST resistant, and 78.3%(83/106) were multidrug-resistant. In the 72 isolates of PRSP and PISP isolated from all clinical studies in spite of GRNX treatment/notreatment, pbpla + pbp2x + pbp2b mutation (39/72) regarding PBP and ermB presence (33/72) regarding the macrolide-resistant gene were observed most frequently. Against infections caused by multidrug-resistant S. pneumoniae, GRNX showed good clinical response as 96.4%(80/83) for clinical efficacy and 100%(81/81) for bacterial eradication.

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