Lenampicillin (KBT-1585) is a new orally active ester derivative of ampicillin (ABPC). Antibacterial activity of KBT-1585 were compared with those of ampicillin, amoxicillin (AMPC) and bacampicillin (BAPC). The results are summarized as follows.
Antibacterial activity of KBT-1585 is ABPC. Then, on the next items, KBT-1585 was almost as active as ABPC and AMPC, and more active than that of BAPC.
1) antibacterial spectrum
2) antibacterial activity against clinical isolates
3) bactericidal activity
4) MIC and MBC
But KBT-1585 differed from ABPC and AMPC in more stability and low inducer activity of β-lactamase.

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In vitro and in vivo antibacterial activities of lenampicillin (KBT-1585), a new oral esterified were examined and the results summarized as follows.
1) KBT-1585 was weaker than ampicillin in terms of bactericidal activity against E. coli NIHJ JC-2, but. after KBT-1585 was treated with human serum, its bactericidal activity was the same as that of ampicillin.
2) On bioautogram of KBT-1585 incubated with each human serum, mouse serum and mouse intestine. homogenate, the antibacterially active spot was observed only at the identical position with ampicillin.
3) MIC and MBC of KBT-1585 were not affected by diacetyl or acetoin which are degradation products of KBT-1585.
4) The maximum serum level of KBT-1585 in mice occured 15 minutes after oral administration, and it. as 5 times as high as that of ampicillin and lower than that of bacampicillin.
5) It was shown that the protective effect of KBT-1585 against experimental infection in mice was the: same as that of bacampicillin and more effective than that of ampicillin.

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The in vitro and in vivo activities of lenampicillin (KBT-1585), a new orally active ester derivative of ampicillin, were compared with ampicillin (ABPC), bacampicillin (BAPC) and talampicillin (TAPC). The following results were obtained.
1. In sensitivity test on clinical isolates, such as Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Haemophilus influenzae, the activities of KBT-1585 were slightly inferior to those of ABPC and equivalent to those of TAPC, but they were superior to those of BAPC.
2. The MICs of KBT-1585 against S. aureus were slightly affected by the pH of the medium, the addition of horse serum, and inoculum size, but they were hardly affected in E. coli.
3. As for the therapeutic effect in experimental intraperitoneal infections in mice, that of KBT-1585 was equivalent or slightly superior to that of ABPC, but they were inferior to that of BAPC and TAPC. In experimental urinary tract infections in mice, KBT-1585 was equivalent or slightly superior to BAPC and undoubtedly superior to ABPC. In experimental respiratory infection in mice, KBT-1585 was inferior to BAPC, but superior to ABPC.
4. The pharmacokinetics of KBT-1585 were investigated in infected mice. The absorption of KBT-1585 was superior to that of ABPC, but inferior to that of BAPC and TAPC.

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Acute toxicity study of Lenampicillin hydrochloride (KBT-1585) was performed with mice, rats and dogs.
The LD₅₀ values of KBT-1585 in male and female rats were ca. 10, 000mg/kg p. o. In parenteral routes its LD₅₀ values were regarded as 4, 362 and 4, 471mg/kg s. c., and 876 and 838mg/kg i. v. in males and females, respectively.
Acute toxicity in mice was slightly potent as compared with that in rats.
In dogs, no death was observed at a dose of 300 mg/kg p. o. KBT-1585, a maximum dose in this toxicity study because of causing emesis. Typical toxic symptoms in mice and rats were sedation, piloerection, clonic convulsion, hypothermia and suppression of respiration.

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Lenampicillin hydrochloride (KBT-1585) was orally administered at doses of 400, 1, 000 and 2, 500 mg/kg to Jcl: SD rats of both sexes for 30 days. The effects of the compound on these rats were investigated in comparison with those observed in rats treated similarly with bacampicillin hydrochloride (BAPC), 2, 500mg/kg. The recovery test was also conducted in rats treated similarly and killed at 28 th day after cessation of drug dosing.
The results obtained were as follows.
1. The rats dosed each KBT-1585 and BAPC showed transient salivation immediately after dosing, seemingly owing to their bitter taste abdominal inflation due to cecum enlargement at high frequency, and increase in water-consumption.
2. Deaths related to drug administration were observed only in BAPC group, being 4 males (23.5%) and 1 female (5.6%).
3. Changes observed in common in KBT-1585, 2, 500mg/kg group and BAPC group were lowered body weight gain in male, increased percent segmented neutrophils and decreased percent lymphocytes in male, increased RBC, WBC and platelets in female, decreased total protein in both male and female, increased A/Gratio and total cholesterol, decreased BUN, Ca⁺⁺, glucose, CRNN, LDH and Al-P in male, decreased Na⁺ infemale, increased adrenal and cecal weights and decreased splenic weights in both male and female.
Changes observed only in KBT-1585 group were decreased GOT in male at doses higher than 1, 000mg/kg, and decreased K⁺ in both male and female and decreased Cl^- in female at 2, 500mg/kg.
Changes observed only in BAPC group were decreased MCV and MCH in both mlae and female, increased reticulocytes in male and decreased total bilirubin in female.
These changes were of those likely to occur in malnutrition and after administration of antibiotics in high doses, and there were obtained, in fact, no anomalous findings in histopathological examination.
5. As a whole, more severe toxic signs were suggested in BAPC group as compared with in KBT-1585 groups.
6. In the recovery test, progress toward recovery was observed when rats were examined at 28 th day after cessation of drug dosing.

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Subacute toxicity study of Lenampicillin hydrochloride (KBT-1585) was performed by oral administration of a daily dose of 625, 1, 250, 2, 500 and 5, 000mg/kg to rats for 3 months, and the following results were obtained.
1) Salivation and soft feces were noted in general symptoms observation.
2) In male-5, 000mg/kg/day group, body weight gain was suppressed. The water intake increased in the groups given 625mg/kg/day or more.
3) Urinary pH lowered in the groups given 1, 250 mg/kg/day or more.
4) In the blood chemical findings, the decrease of total protein K⁺, and Cl^-, cecum the increase of A/G ratio and Na⁺ were observed.
5) In pathological study, the increase of the weight in liver, kidney, cecum and adrenal gland was confirmed. The swelling of centrilobular hepatocyte and adrenal cortex was observed in pathomorphological examination.
In conclusion, no toxicological evidence such as death and damage to any organ by cumulative dosing were confirmed even in the group given 5, 000 mg/kg/day.

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Subacute toxicity of lenampicillin hydrochloride (KBT-1585), a new ampicillin prodrug with excellent enteral absorbancy, was examined in dogs by oral administration at a daily dose of 100, 300 and 900 mg/kg for three consecutive months. The typical findings associated with the drug were vomiting, salivation, the increase of water intake and A/G ratio, the decrease of total protein and urinary pH, and the erosion of the gastric mucosa. Above toxic findings were substantially similar to those of the other ampicillin derivatives in the incidence and extent.
It was resulted that KBT-1585 might be low toxic antibiotic and its maximum oral non-toxic dosage in dogs was 100 mg/kg/day in this study.

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Chronic toxicity study of lenampicillin hydrochloride (KBT-1585) was performed by repeated oral administration of a daily dose of 75, 150 and 300 mg/kg to beagle dogs for 6 months and the following results were obtained.
1) No death was occurred.
2) Selivation, vomiting and slight diarrhoea were observed in the groups of higher doses.
3) Serum total protein in male-300 mg/kg/day group decreased slightly at the sixth month examination.
4) No abnormal findings were detected in body weight gain, food and water consumption, urinalysis, blood pressure, E. C. G., hematological examination, oph thalmological examination, organ weights and pathological examination.
5) Above findings were recovered easily by withdrawal for 5 weeks.
Considering these results, it was concluded that 75 mg/kg/day was the maximal non-toxic dose of KBT-1585 in 6 months chronic oral toxicity study in dogs.

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Study on teratological effects of lenampicillin hydrochrolide (KBT-1585) in pregnant Wistar-Imamichi rats carried out by repeated oral admnistration of a daily dose of 100, 500, 2, 500 mg/kg during organogenetic period from day 7 to 17 of gestation. The main results are as follows;
1. Salivation in the 2, 500 mg/kg/day group, and slight suppression in body weight gain, decrease in food consumption, increase in water intake and enlargement of cecum in the 500 and 2, 500 mg/kg/day groups were observed.
2. As to the cesarean section findings, no changes attributable to lenampicillin treatment were obseved.
3. In the observations of (F₁) offspring, no significant difference was observed between the treated groups and the control group in terms of survival body weight gain, reproductive performance, behavior and learning ability.
From the findings mentioned above, it is concluded that the maximum non-effect level on the fetuses and offspring is 2, 500 mg/kg under the present experimental condition.

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The immunological properties of Lenampicillin hydrochloride (KBT-1585) were compared with ABPC. Rabbits were immunized by each KBT-1585 and ABPC with complete Freund's adjuvant, mice by each KBT-1585-and ABPC-keyhole limpet hemocyanin conjugate with Al(OH)₃ gel, specific antibodies (IgM, IgG and IgE) were found in sera. Antibody-producing activity of KBT-1585 was slightly weaker than that of ABPC, and KBT-1585 had cross-reactivity with ABPC.
From these results, it is suggested that antigenicity of KBT-1585 is attributed to ABPC moiety in its molecule.

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The mutagenicity of Lenampicillin hydrochloride (KBT-1585), diacetyl, acetoin and 2, 3-butanediol was tested using S. typhimurium TA 100, TA 1535, TA 98, TA 1538, TA 1537 and E. coli WP 2 uvr A.
The micronucleus test using mouse bone-marrow cells was also conducted for KBT-1585 and diacetyl.
The results were as follows;
1. Reverse mutation test in bacteria
KBT-1585 exhibited no demonstrable mutagenicity for any of the above bacterial strains in the absence or presence of S-9 mix by a preincubation method. Diacetyl, acetoin and 2, 3-butanediol exhibited no demonstrable mutagenicity to all these strain at the concentration ranging from 1 to 5, 000μg/plate by a plate method.
2. Micronucleus test in mice
The frequency of the micronucleated polychromatic erythrocytes in the bone-marrow of mice treated with KBT-1585 did not differ significantly from that in the control group, although the polychromatic erythrocytes decreased significantly in the group treated with KBT-1585. There was no difference in the frequency of the micronucleated polychromatic erythrocytes between the diacetyl treated group and control group.
In conclusion, it was suggested that KBT-1585, diacetyl, acetoin and 2, 3-butanediol had no mutagenic activity in bacteria, and that both KBT-1585 and diacetyl bad no micronucleus-inducing capacity in the mouse bonemarrow erythrocytes.

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Effects of ABPC, lenampicillin (KBT-1585), BAPC and TAPC on the microbial flora were compared in mice by dosing of each 20mg potency/kg, twice a day for 3 days. ABPC and BAPC were accompanied by significant changes in the microbial flora in every regions studied of the gastrointestinal tract, especially overall decrase of Lactobacilli and the increase of Enterobacteriaceae in the cecum and large intestine, while KBT-1585 and TAPC were accompanied by the decrease of Lactobacilli alone.
In the cecum, the enlargement and the increase of wet weight were observed in ABPC, BAPC and TAPC treated mice but not in KBT-1585.

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General pharmacological properties of ampicillin (5-methyl-2-oxo-1, 3-dioxolene-4-y1) methyl ester hydrochloride, lenampicillin (KBT-1585), a new ampicillin prodrug, were studied and the following results were obtained.
1. KBT-1585, in the dose range of 30-1, 000mg/kg p. o., was found to have no effects on the central nervous system, as shown in the studies of the general observation and body temperature in rats, the spontaneous EEG in rabbits, and the locomotor activity, pentobarbital-induced anesthesia, convulsions induced by either electroshock, pentetrazol or strychnine, muscle relaxant action and analgesic effect in mice. The only effect observed in the general observation study in rats, however, was the transient increase of salivation and respiratory irregularity, being presumably concomitant to salivation, at a high dose of 3, 000mg/kg p. o.
2. Effects of KBT-1585 on the autonomic and somatic nervous systems were studied on the nictitating membrane and neuromuscular junction in dogs at a dose of 100mg/kg i. v., corneal reflex for local anesthetic action in guinea pigs by topical application of 0.3, 1.0 and 3.0% solution, bile secretion in rats at a dose of 30mg/kg i. v., and gastric secretion in rats at doses of 30, 100, 300 and 1, 000mg/kg, intraduodenally. Any effects thus observed were only the transient inhibition of corneal reflex by 3.0% solution and the reduced. gastric secretion at a dose of 1, 000mg/kg i. d., the extent of reduction being less than that produced by atropine.
3. Effects of KBT-1585 on the respiratory and cardiovascular systems were studied in vivo in anesthetized. dogs, in situ in anesthetized dogs, and in vitro using isolated, blood-perfused canine heart preparations. As a. whole, effects of KBT-1585 on the parameters determined were found to be slight and transient, and the respiratory and cardiac movements tended to be depressed and the peripheral vascular beds tended to be dilated.
4. In the isolated smooth muscle preparations, KBT-1585 was shown to have almost no effects on their tonus and spontaneous motility in high concentration of 10^-4M, except for the inhibition of motility of isolated non-pregnant rat uterus. KBT-1585 inhibited, to some extent, the ACh and histamine-induced contraction of the isolated guinea pig ileum preparations in high concentration of 10^-3M. There was no significant effect on the passage of charcoal meal through small intestine in mice.
5. As to the other properties, KBT-1585, 100-1, 000mg/kg p. o., produced gastric mucosal injury in rats, but it was weaker than that of aspirin. In saline loaded rats, KBT-1585, 1, 000mg/kg p. o., reduced urine volume and pH value. There were no significant effects on the blood glucose level and blood coagulation in rabbits, and carrageenin-induced edema in rats.

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Absorption, distribution and excretion of a new ampicillin (ABPC) prodrug, lenampicillin hydrochloride (KBT-1585), was investigated in compared with bacampicillin (BAPC) in rats and dogs, and the following results were obtained.
1. The peak concentration (Cmax) of ABPC in plasma were reached 1 hr. in rats and 30 min. in dogs after oral administration of KBT-1585.
In dogs, Cmax and the area under the plasma concentration curves (AUC) were significantly higher than those obtained for BAPC.
2. The absorption studies using in situ loop techniques in rats showed KBT-1585 was predominantly absorbed from small intestine.
3. The oral administration of KBT-1585 in rats gave a slightly higher and earlier ABPC concentration in tissues than those after BAPC.
4. The lower concentration of ABPC in fetus was observed only 1 hr. after oral administration of KBT-1585 to pregnant rats.
The concentration of ABPC in milk were 1/2 to 1/3 of those in maternal sera.
5. The urinary excretion of ABPC were 24.5% in rats, 45.2% in dogs after oral administration of KBT-1585, while 18.4% in rats, 12.2% in dogs after BAPC.
6. Binding of KBT-1585 to rat, dog and human serum protein were 12.3%, 19.2% and 30.0%, which were similar to those of ABPC.

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Lenampicillin (KBT-1585), an ampicillin (ABPC) prodrug, was administered orally to 11 healthy adult male volunteers to study the safety and pharmacokinetics.
In single dose studies, 5 volunteers received 250mg (equimolar to 250mg of ABPC) and 500mg (equimolar to 250mg of ABPC ×2 tablets) of KBT-1585 without food in early morning. In multiple dose studies, 6 volunteers were given 250mg of KBT-1585 q. i. d. in all 25 times for a week. Multiple dose studies were investigated after confirming the safety of KBT-1585 in single dose studies.
In single dose studies, as the mean peak serum concentration of ABPC, 4.86μg/ml was obtained for a 250mg and 10.45μg/ml for a 500mg, respectively within one hour. The biological half life was about one hour, independing on the dose. The urinary level reached maximum concentration in 0-2 hours. About 50% of the given KBT-1585 was recovered as ABPC in 12 hours.
In multiple dose studies, the mean peak serum concentration of ABPC and the urinary rate of ABPC were invariable everytime examined. It was, therefore, suggested that no accumulation in tissues was observed.
No abnormalities were observed in subjective and objective symptoms, physical test results, or laboratory test results at all these studies.

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Lenampicillin (KBT-1585), a new oral ampicillin prodrug, has been investigated.
A pharmacokinetic study of KBT-1585 was conducted in 6 healthy male volunteers in fasting and after meal following the single oral dose of KBT-1585 equivalent to 250mg of ampicillin. The mean peak serum level was 7.02μg/ml at 30 minutes in fasting state and 4.82μg/ml at one hour in after meal, respectively. Half life in serum was 0.8 hour approximately. The urinary excretion rates were 52.2% in fasting state and 47.5% in after meal during 8 hours, respectively.
Thirty nine patients with respiratory tract infections and urinary tract infections were treated with KBT-1585 of 1, 000mg q. i. d. dose in 3 to 9 days. Nineteen patients of all were cured excellent, 18 were good, one was fair and one was poor. The effective rate was 94.9%. One patient was occured mild nausea and no laboratory abnormalities were observed.

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The clinical efficacy of lenampicillin (KBT-1585) was studied in the field of internal medicine, and the following results were obtained.
1) Clinical effect: In the treatment of 49 cases with respiratory tract infections, the clinical responses were excellent in 9 cases, good in 35 cases, fair in 3 cases and poor in 2 cases. The clinical effectiveness was 89.8%.
In the treatment of 24 cases with urinary tract infections (UTI), the responses were excellent in 10 cases, good in 10 cases, fair in 2 cases and poor in 2 cases. The clinical effectiveness rate was 83.3%.
2) Bacteriological effect: As the causative bacteria of the present cases with upper respiratory tract infection, S. pyogenes, S. viridans and S. epidermidis were isolated. S. pneumoniae, S. aureus, H. influenzae, Klebsiella species and P. aeruginosa were isolated in the patients with lower respiratory tract infection. In, the patients with UTI, E. coil was most frequently isolated (19 strains). As another bacteria, S. epidermidis, K. ozaenae and P. mirabilis were isolated.
These were completely eliminated in 29 strains, decreased in 5 strains and unchanged in 2 strains, following the treatment of KBT-1585.
3) Side effect: The incidence of side effect was low. Diarrhoea, headache and anorexia were occurred in each one case. Eosinophilia in 3 cases, anemia in 2 cases and leucopenia in 1 case were observed after the administration of KBT-1585.
KBT-1585 was considered to be useful antimicrobial agent for the treatment of mild infections in the field of internal medicine.

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32 patients with respiratory tract infections, four with acute pharyngitis, two with acute tonsillitis, four with acute pharyngitis and acute bronchitis, 12 with acute bronchitis, seven with chronic respiratory tract infection and three with acute pneumonia, were treated with oral administration of 750 to 1000mg a day of lenampicillin (KBT-1585). Clinical response was good in 22 patients, fair in seven and poor in three.
No adverse symptom and sign was noted during administration of KBT-1585.
Slight elevation of GPT was observed in two cases.

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Lenampicillin (KBT-1585) was administered to a total of 40 patients with respiratory tract infections including 11 cases of pneumonia, 18 cases of acute exacerbation of chronic bronchitis, 10 cases of acute bronchitis and one case of diffuse panbronchiolitis.
The drug was administered orally at a daily dose of one gram for 7 days (25 cases), 14 days (9 cases), 21 days (one case) and three days (one case), three days and one dose (one case), 4 days (two cases), 6 days and one dose (one case).
The following 25 potential pathogens were recovered from the sputum at a start of the treatment with KBT-1585 and four pathogens of H. influenzae which had β-lactamase were not eradicated during the treatment (eradication ratio=84%).
The clinical response to the treatment with KBT-1585 was excellent in 15 cases, good in 20 cases, fair in one case and poor in four cases (efficacy rate=87.5%).
A rash was observed in one case after four days of administration but it was so slight and eosinophilia and feeling of nausea were observed in one case each.
From the above results, it is concluded that KBT-1585 is one of effective and useful prodrug of ampicillin.

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Lenampicillin (KBT-1585), 1, 000 mg/day, was administered orally to 22 patients with respiratory tract infections, and the following results were obtained.
Clinical response of KBT-1585 was excellent in 2 patients, good in 10, fair in 5, poor in 4 and undetermined in 1, thus overall efficacy was 57.1%.
An epigastralgia occurred in one case as side effect. However, this symptom disappeared immediately after discontinuation of the administration without any other special treatment. Laboratory tests revealed an eosinophilia in two cases, although this finding was alleviated rapidly following cessation of the therapy. No severe side effects caused by the drug were observed.

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Lenampicillin (KBT-1585) was administered to ten patients. In five cases with acute bronchitis, one case with acute cystitis, two cases with acute pyelonephritis and one case with chronic pyelonephritis good effects were observed. But KBT-1585 was not effective in one patient with bronchopneumonia.
No side effects nor abnormalities of laboratory findings were observed.

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Basic and clinical examinations were made on Lenampicillin (KBT-1585).
The MICs of KBT-1585 against clinical isolates such as S. faecalis, Proteus (indole+), E. coil and H. influenzae were determined and compared with those of ABPC, CEJC, CXD and CCL against the same organisms. The MICs of KBT-1585 were almost same as those of ABPC.
In the clinical studies, daily doses of 750-1, 000mg of KBT-1585 were administered orally for 3-14 days to 25 patients, including 19 cases with respiratory tract infections and 6 cases with urinary tract infections The clinical efficacy was good in 16 cases out of 24 cases (efficacy rate: 66.6%), in another case the administration was discontinued because of side effect (rash).
As to side effects, vertigo in one case and skin rash in one case were observed, and no abnormal laboratory findings were observed.

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Lenampicillin (KBT-1585), a new ampicillin prodrug, was used for the treatment of 26 cases with bacterial respiratory infections orally.
The results were that KT-1585 was effective in 40.9% of 22 cases with lower respiratory tract infection and in 75.0% of 4 cases with acute pneumonia. Four cases with S. pneumoniae and one case with S. aureus were all eradicated after treatment, but 5 in 16 cases with H. influenzae were not eradicated.
As a side effect, mild leukopenia, eruption and epigastralgia were found in each one case.
We concluded that, KBT-1585 was an effective antibiotic in the treatment of respiratory infections.

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Studies on Lenampicillin (KBT-1585), a new synthetic antimicrobial agent of penicillin, were carried out with respect to its absorption, excretion, clinical responses in the field of internal medicine and side effects.
(1) Absorption and excretion: The mean peak blood concentration was 5.89μg/ml after a single dose of 250mg without food within 0.5 hours, which was higher than the amount of AMPC at the same dose level. The concentration declined with a half-life (T_1/2) of about 0.84 hours. About 51.9% of the given KBT-1585 was recovered in the urine within 6 hours after administration. In comparison with this recovery rate of KBT-1585, that of AMPC was 53.6%. The blood half-life had a tendency to delay (AMPC T_1/2: 1.36 hours) and the urinary recovery rate was declined with the pre-administration of probenecid.
(2) Clinical responses: KBT-1585 was administered to 6 cases and gave following results; excellent in 1 case, good in 4 and fair in 1 (efficacy rate; 83.3%). 5 cases among 6 in which the bacteriological evaluation could be judged, the eradication rate was 80.0%.
Neither side effects nor abnormal clinical laboratory findings were observed.

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Lenampicillin (KBT-1585), a new derivative of ampicillin was administered to 9 patients, consisting of 4 cases of acute bronchitis, 1 case each of acute tonsillitis, bronchiectasis, acute pharyngitis, acute bronchitis with laryngitis and acute cystitis.
The pathogens were Staphylococcus aureus in 1 case of acute tonsillitis, Haemophilus influenzae in 1 case of bronchiectasis and Escherichia coli in 1 case of acute cystitis.
This antibiotic drug was given orally at a dose of 0.25g, 3-4 times a day for 3-7 days and the total doses were 2.25-7.0g
The clinical efficacy was good in 4 cases, fair in 3 cases, poor in 1 case and unknown in 1 case.
As for the bacteriological effects of KBT-1585, organisms were eradicated in two cases (H. influenzae: 1, E. coli: 1). However, organisms in 1 case of S. aureus persisted. In the other 6 cases the bacteriological effects were not evaluable.
No side effect was observed in all cases. Regarding abnormal laboratory findings, slight increase of S-GOT in 1 case and that of S-GOT and S-GPT in 1 case were observed.

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Lenampicillin (KBT-1585), a newly developed oral prodrug of ampicillin, was studied for its clinical efficacy.
KBT-1585 was used in the treatment of 13 cases of respiratory infectious disease comprising 9 cases of acute bronchitis, 2 cases of pneumonia, one case of acute pharyngitis and one case of bronchiectasis with infection.
KBT-1585 was administered orally at a dose of 750-4, 000 mg, 30-4 times daily for 4-42 days and results obtained were good in 11 cases, fair in one case and poor in one case, effective rate being thus 84.6%.
Adverse reaction such as drug eruption, drug fever, nausea, vomiting, diarrhoea and abnormal laboratory findings were not obtained.
From the above clinical experiences, KBT-1585 would be a clinically useful antibiotic against respiratory infectiousdisease.

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The effect of lenampicillin (KBT-1585) was clinically evaluated in 7 cases of acute respiratory infection (acute bronchitis 4 cases, pneumonia 1 case and bronchopneumonia 1 case) and one case of urinary tract infection. KBT-1585 was orally administered 250 mg three of four times a day.
Good clinical response was observed in 5 cases. The effective rate in total was 71.4%. Skin rush appeared five days after administration in one patient in whom clinical response was poor. This case was evaluated non response one.
From the results, it was considered that KBT-1585 would be expected to be useful for the treatment of outpatients with acute respiratory infection or urinary tract infection.

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Lenampicillin (KBT-1585) was administered to 14 patients with various infectious disease (chronic pyelonephritis; 2, acute cystitis; 2, pneumonia; 2, acute bronchitis; 5, chronic bronchitis; 1, acute pharyngitis; 2). This medication was given by per as at a daily dose of 0.75-1g. The clinical efficacy was good in 8 cases, fair in 5 cases, poor in 1 case. In 1 case Al-P increased slightly but no other adverse reaction was observed.

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Lenampicillin (K13T-1585) is an ampicillin prodrug for oral administration, synthesized by Pharmaceuticals Research Center, Kanebo Co., Ltd. Absorption and urinary excretion of this drug were investigated and clinical efficacies in 19 cases were evaluated and following results were obtained.
Concentrations of Kl3T-1585 and ampicillin in serum and urine after single oral administration of 250 rug were measured in 10 healthy adult volunteers by a cross over method in fasting. The mean peak serum concentration was 6.0 μg/ml, which was twice as high as that of ampicillin, 2.7 μg/ml. The concentration of KBT-1585 declined rapidly but both the half-lives of both drugs were not so different. Urinary excretion within 6 hours was 54.5 %, which was not so different from that of ampicillin, 45.7 %.
KBT-1585 was administered at a dose of 250 mg three or four times a day 4-14 days. In 10 cases with acute bronchitis, 1 with chronic bronchitis, 7 with acute tonsillitis, 7 with acute tonsillitis and 1 with acute cystitis the therapeutic effect of the drug was estimated as good in 16 cases, fair in 2 cases and poor in 1 case.
As the causative bacteria, H. influenzae and H. parainfluenzae were most frequently isolated. These were completely eradicated in 9 cases, replaced other strain in 1 and unchanged in 3.
From these results, KBT-1585 as an oral antibacterial agent is evaluated to be useful except for the treatment of serious infections.

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New oral penicillin, Lenampicillin (KBT-1585) was evaluated in 9 cases (aged patients) with various infections. KBT-1585 was administrated orally at the dosage of 0.75 to 1 g for 5 to 7 days. Satisfactory results were obtained in 2 bronchitis, 2 pyelonephritis and one of 5 chronic cystitis. Skin itching and eosinophilia were noted in one of 9 cases.

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Lenampicillin (KBT-1585), a newly developed ampicillin prodrug, was evaluated clinically in 32 patients with respiratory tract infections. The clinical responses of acute tonsillitis were good in all the 4 cases, those of 27 acute bronchitis, were good in 19 cases and in one case with poor compliance, and that of one case of chronic bronchitis was good. The overall efficacy rate was 77%. Neither side effects nor abnormal clinical laboratory findings were observed. From the above results, it is suggested that KBT-1585 is a useful antibiotic for respiratory tract infections.

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Clinical investigation was carried out on lenampicillin (KBT-1585), a new oral prodrug of ampicillin and the following results were obtained.
1. KBT-1585 was applied for a total of 18 cases with mild and moderate respiratory tract infections (RTI) and 4 cases with urinary tract infections (UTI). The clinical results obtained were good in 14 (77.8 %) out of the 18 cases of RTI and good in all UTI.
2. Side effect was observed in 2 cases: one showed rash and the other showed eosinophilia.

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Lenampicillin (KBT-1585), a newly developed ampicillin prodrug, was clinically evaluated in 28 cases including pneumonia (2 cases), acute bronchitis (16), acute tonsillitis (4), acute exacerbation of chronic respiratory tract infection (5) and acute pyelitis (1).
Therapeutic effective rate was 100% in pneumonia, tonsillitis and pyelitis, 80% in bronchitis and 40% in chronic respiratory tract infections (chronic RTI).
The strains of H. influenzae and E. coli were isolated from a case with acute exacerbation of chronic RTI and a case with pyelitis, respectively. Both of them were eradicated by the administration of KBT-1585.
Clinically the former case gave an excellent result and the latter showed a good effect. In another case with acute excerbation of RTI, a strain of Enterobacter replaced normal flora and this case showed clinically a fair result.
Adverse effects such as gastro-intestinal disorders were observed in 4 cases and therefore one of them discontinued to take on his own authority.
However they recovered rapidly after the cessation of the drug administration.
Abnormal laboratory findings were noted in 3 cases, eosinophilia in 1 case, eosinophilia and leucopenia in 1 case and elevation of GOT and GPT in 1 case. These abnormal findings returned to normal after cessation of the drug administration.

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Lenampicillin (KBT-1585), a new orally active prodrug of ABPC, was applied to the treatment of 18 patients with respiratory tract infections.
The drug was administered orally, 0.75-1.0 g/day, divided into three or four doses, for the period of 3-24 days.
The results were as follows excellent in three cases, good in ten cases, slightly good in three cases, ineffective in two cases (one case was far advanced bronchiectasis with symptomatic aggravation caused by P. aeruginosa, and the other was intractable empyema complicated by diabetes mellitus and bronchial asthma).
Diarrhoea, presumably as side effect, was observed in one case.
Usefulness of the drug for the treatment of respiratory tract infections, especially of acute infections such as pharyngitis, tonsillitis and pneumonia, was suggested.

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Lenampicillin (KBT-1585), a prodrug which exerts its activity as ampicillin in the body, and whose meta. bolites are natural substances (acetoin and 2, 3-butanediol), was examined on its clinical availability. The results obtained were as follows:
Fifty-two patients with infectious diseases were treated with KBT-1585 (750-1, 000mg/day). The clinical effectiveness could be evaluated in 50 of the cases.
Thirty-one out of 42 cases with respiratory tract infections responded to the therapy with excellent or good results (effective ratio: 73. 8%). Five out of 7 cases with urinary tract infections also well responded to the therapy (effective ratio: 71.4%). The drug was also effective in one case of acute colitis.
None of the 52 patients showed any untoward reactions clinically, although slight abnormalities in laboratory fi ndings (slight elevation of SGOT and/or SGPT) attributable to the drug therapy were observed in four of the cases.
These results obtained may suggest an ample clinical availability of the drug comparable to other new β-lactam antibiotic preparations for oral use.

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Lenampicillin (KBT-1585), a newly synthesized ABPC prodrug, was administered to healthy adult subjects to compare its bioavailability with that of talampicillin (TAPC), and used clinically in patients with various infections to evaluate the clinical efficacy in the field of, internal medicine. The results obtained were as follows:
1) Absorption and excretion: KBT-1585 and TAPC in a single dosage of 250 mg (ABPC equivalent) were administered to 6 healthy adult subjects in fasted and non-fasted state, respectively, and serial serum and urinary levels of ABPC were examined using a cross over method.
The mean serum peak levels of ABPC in fasted subjects were 5.45 μg/ml(1 hr. after) and 4.36μg/ml (1 hr. after) in KBT-1585 and TAPC groups, respectively, whereas in non-fasted subjects were 3.36μg/ml (1 hr. after) and 1.86μg/Inl (3-4 hrs. after) in KBT-1585 and TAPC groups, respectively.
The mean urinary recovery rate of ABPC within 6 hrs. in fasted subjects were 50.2 and 45.6 % in KBT-1585 and TAPC groups, respectively, whereas in non-fasted subjects were 41.2 and 39.6 % in KBT-1585 and TAPC groups, respectively. In particular, as for the recovery within 2 hrs. in non-fasted subjects, the KBT-1585 group revealed significantly higher value than the TAPC group.
2) Clinical efficacy: KBT-1585 was administered orally to 20 patients with acute pharyngitis (2 cases), acute tonsillitis (2 cases), acute bronchitis (2 cases), acute exacerbation of chronic bronchitis (5 cases), chronic bronchitis (2 cases), infected bronchial asthma (1 case), infected bronchiectasis (1 case), pneumonia (3 cases), infected lung cancer (1 case) and acute cystitis (1 case) at a daily dosage of 1, 000 mg (ABPCequivalent) except for 1 case (750mg/dey) for periods of 3 to 21 days.
The clinical efficacy was “excellent” in 3, “good” in 13, “fair” in 1, “poor” in 2, and “excluded from the clinical evaluation” in 1 case.
A slight increase in GPT in 1 case and epigastric discomfort in 1 case were noted. No other side effect or abnormal finding in laboratory examination was observed.

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Lenampicillin (KBT-1585) was administered to 21 cases with respiratory tract infection and 1 case with acute otitis media, at a dose of 0.75-1.0g per day for 4 to 14 days. Clinical effects were excellent in 3, good in 14 and fair in 4 cases. The clinical efficacy rate in all 21 cases was 80.9 percent. The bacteriologiccal eradciatio n rate of 18 strains obtained from sputum was 55.5 percent.
As a side effect of KBT-1585 nausea and anorexia in 1 case and the feeling of a full stomach in 1 case was observed, but these symptoms were mild. Two cases of a slight eosinophilia were observed. From these results KBT-1585 was considered valuable drug for the treatment of respiratory tract infections.

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Lenampicillin (KBT-1585), a prodrug of ampicillin, was administered to 6 cases of respiratory tract infections, each one case of acute tonsillitis, chronic bronchiolitis and chronic bronchitis and 3 cases of upper respiratory tract infection, at a daily dose of 1, 000 mg for 7 to 14 days.
Excellent results were obtained in 2 cases, good in 2 cases, fair in one case and poor in one case.
No side effect was observed.

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The clinical effects of lenampciillin (KBT-1585) were studied in 6 patients, 2 with chronic bronchitis, 2 with bronchiectasis, 1 with pneumonia and 1 with lymphadenitis.
This antibiotic was administered 1.0 g a day orally for 4-45 days.
Clinical results were good in 2 cases, fair in 1 case, poor in 2 cases and undetermined in 1 case with lymphadenitis. The rate of effectiveness was 40.0%.
Bacteriological responses were not observed.
No side effect was observed.

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Laboratory and clinical studies were performed on lenampicillin (KBT-1585), a new prodrug of ampicillin (ABPC), and results were as follows.
1. Antimicrobial activities: MICs of KBT-1585 against various clinical isolates were determined. With the inoculum size of 10⁶ cells/nil, percentages of strains susceptible to 12.5 μg/ml or less were S. aureus 89%, S. faecalis 96%, E. coli 52%, Proteus sp. 54%, Salmonella sp. 80%, Shigella sp. 100%, S. marcescens 4%. These activities were almost equal to those of ABPC.
2. Serum concentration and urinary excretion rate: Serum concentrations of ABPC were measured in 4 healthy volunteers, given 250 mg of KBT-1585 by oral administration at fasting. The peak of mean serum concentrations of ABPC was 9.0μg/ml at 30 min. and T1/2 was 0.63 hours. Urinary excretion rate of ABPC was 52% at 8 hours after the administration.
3. Clinical efficacy: One patient with pneumonia, 6 with bronchitis, 3 with pharyngitis, 1 with sinuitis, 1 with pyelonephritis and 1 with submandibular tumor were treated with KBT-1585 daily dose of 0.5-1.5g for 2-21 days. Clinical responses were excellent in 1, good in 7, fair in 2 and unknown in 3 cases. Side effects were observed in 2 patients, no change was in laboratory findings.

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Laboratory and clinical studies on lenampicillin (KBT-1585), a newly developed ampicillin prodrug, were carried out with following results.
1) Antibacterial activity: The in vitro antibacterial activity of KBT-1585 was tested by the serial microbroth dilution method using MIC 2000 system (Dynatek Co.). The minimum inhibitory concentrations (MICs) of ABPC against total 433 strains consisting of 26 standard strains and 407 clinical isolates including Staphylococcus aureus 48, Staphylococcus epidermidis 42, Streptococcus pneumoniae 48, Streptococcus faecalis 44, Escherichia coli 52, Klebsiella aerogenes 49, Proteus mirabilis 47, Haemophilus influenzae 63 were compared with those of amoxicillin (AMPC), mecillinam (MPC) and piperacillin (PIPC). Antibacterial activities of ABPC against S. aureus, S. epidermidis and S. faecalis were almost equal to those of AMPC, and more potent than those of PIPC and MPC. AMPC and PIPC were two times more active than ABPC against S. pneumoniae.
On the other hand, antibacterial activities of ABPC and AMPC against Enterobacteriaceae such as K.aerogenes, E. coli and P. mirabilis were less potent than those of PIPC and MPC. PIPC was most active against H. influenzae and followed by ABPC and AMPC.
2) Serum and sputum levels in patients with chronic respiratory tract infection: Two patients with chronic respiratory tract infections were objected in this study. After a dose of 500 mg of KBT-1585 was given to them orally, their levels in sera and sputa were measured by bioassay method. As a result, peak serum levels were obtained at one hour after administration showing values of 6.39 to 10.64μg/ml.
On the other hand, concentrations of sputum reached its peak at 4 to 6 hours after administration in one case with purulent sputum and the value was 0.38μg/ml. But in one case, the value was under the limit of measurement.
3) Clinical evaluation and adverse reaction: Forty patients with respiratory infections (pneumonia 16, chronic bronchitis 15, bronchiectasis 8, organizing pneumonia 1) were treated with 0.75 to 1.0 g of KBT-1585 daily for 3 to 21 days by oral administration. Twenty-nine of 39 patients responded satisfactorily to the treatment and the efficacy rate was 74.4%(excellent 9, good 20, fair 5, poor 5, unknown 1). Subjective and objective symptoms, hematological and biochemical data and renal functions were checked up before and after administration of KBT-1585.
Abnormal laboratory findings were observed in 3 cases: elevation of S-GOT in 1, BUN in 1 and Al-Pase in 1.

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Lenampicillin (KBT-1585) is a new orally well-absorbed derivative of ampicillin. Laboratory and clinical studies have been performed on KBT-1585 in order to evaluate its usefulness in respiratory infections.
In vitro antibacterial activity of KBT-1585 against 164 isolates of 4 pathogens of respiratory infection, i. e., Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae and Branhamella catarrhalis, was measured comparing with other penicillins and cephems.
MIC₅₀ of KBT-1585 against S. pneumoniae (48 strains) was 0.025 μg/ml, H. influenzae (27 strains) 0.39 μg/ml, B. catarrhalis (62 strains) 0.78 μg/ml and S. aureus (27 strains) 25 μg/ml.
The penetration rate of KBT-1585 from blood into sputum was measured and the ratio of sputum peak level v. s. serum peak level was ranged from 2.8 to 7.2%.
KBT-1585 was orally administered to 29 patients with respiratory infections; acute bronchitis 6, chronic bronchitis 15, chronic pulmonary emphysema 6, chronic bronchiolitis 1 and bronchiectasis 1. The dosage used was 750 to 1, 500 mg administered orally 3 to 4 time a day. Clinical response of KBT-1585 treatment in 29 cases was excellent in 6, good in 19 and fair in 4. So, clinical cure was obtained in 25 (86.2%) of 29 patients. No clinical side effect was observed. One of whom also developed mild eosinophilia and elevated transaminase were noted in two patients.
Considering from the above results, it is concluded that KBT-1585 is one of the superior antibiotics against respiratory infections.

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Twelve patients with respiratory tract infection were treated with lenampicillin (KBT-1585) which was prodrug of ampicillin and had a broad spectrum of antibacterial capacity against gram-positive and-negative bacteria.
Nine of 12 patients responded satisfactorily to the treatment and effectiveness rate was 75 %(excellent 2, good 7, poor 3).
One of the cases complained of appetite loss, vertigo and skin eruption three days after administration. Hematological and biochemical examinations of blood revealed no abnormality except for one patient who showed the elevation of serum GPT.
These results show that KBT-1585 is one of the useful antimicrobial agents in the chemotherapy of respiratory tract infections

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Basic and clinical studies were conducted on a new ampicillin prodrug lenampicillin (KBT-1585) and the following results were obtained.
Orally administered KBT-1585 has an activity as ampicillin in the body, and the antibacterial activity of ampicillin to clinical isolates was studied. Antibacterial activity of ABPC to coagulase positive Staphylo. cc. and coagulase negative Staphylo. cc. were examined, and proved to be equal to AMPC and more potent than CEX and CCL. ABPC showed strong activity to S. faecalisand moderate activity to B. fragilis. However, almost all strains of K. pneumoniae, E. cloacaeand P. aeruginosa were resistant to it.
KBT-1585 (500 mg) was administered orally without meal to three healthy adults and their mean peak serum level was 16.3 μg/ml at one hour after administration, afterward the level rapidly decreased, and mean serum level of 0.3μg/ml was at 4 hour after administration.
KBT-1585 was administered to 37 cases of surgical infections mainly skin and soft tissue infections. The overall effective rate was 81.1%. No side effect or abnormal laboratory findings were observed except one case of slight nausea.

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Fundamental studies on lenampicillin (KBT-1585) were investigated for its clinical use.
KBT-1585, a prodrug of ampicillin (ABPC), showed a broad spectrum of antibacterial activity against gram-positive and gram-negative bacteria.
Its susceptibility were good for clinical isolates from surgical specimens, such as S. aureus, S. epidermidis and E. coli but many resistant strains, which MIC was≥25 μg/ml, were observed in K. pneumoniae, E. cloacae, S. marcescens and P. aeruginosa.
We studied absorption and excretion of KBT-1585 and the following results were obtained.
High serum concentration were rapidly attained by its oral use. The mean peak serum level was 12.9μg/ml at 30 min. after a single oral administration of 500 mg KBT-1585, and its half life was 1 hour.
The mean urinary excretion rate was 75% at 8 hrs. after administration.
Bile concentration showed the peak level 10.34 μg/ml and its recovery rate, 0.16%, 1 hr. after 500 mg oraladministration.Pharmacokinetic parameters of serum concentration of bioassay and HPLC were following respectively Ka (hr^-1): 8.03, 50.5, K_el (hr^-1): 0.80, 1.10, T_1/2 (β)(hr): 0.86, 0.63, V_d (1): 29.3, 29.8, AUC (hr·μ/ml) 22.2, 15.2.
By the results of examination about the metabolism of KBT-1585 with TLC and bioautogram of human urine, we proved that KBT-1585 was excreted as ABPC and no active metabolite detected in body.
After a single oral administration of 20 mg of KBT-1585, tissue concentration were liver>kidny>serum>heart>lung>spleen>muscle.

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A clinical investigation of lenampicillin (KBT-1585) in 109 patients with skin and soft-tissue infections obtained the following results in surgery.
1. When the clinical efficacy was evaluated by the doctors in charge, the overall effect was excellent in 15 cases, effective in 64, fair in 24, and failure in 6, with an overall clinical efficacy rate of 72.5%.
The clinical efficacy rate was as high as 77.8-100% in considerable number of patients with infected atheroma, furuncle or phlegmon. But the clinical efficacy rate in patients with abscess was as low as 40%. The efficacy rate was 69.2 % in patients with who did not respond to treatment with other antibiotics such as cephalexin or bacampicillin.
2. The eradication rate of the organisms islated was 80.6%.
3. No significant differences were observed between the clinical efficacy in patients with and without surgical intervention in clinical or bacteriological efficacy. There was a clinical efficacy rate of 70.1 % in 87 patients who had associated with surgical procedures. In those patients who did not require surgical procedures the clinical efficacy rate was 81.8%.
4. Side effect was recognized in one patient to be eruption. No abnormal changes due to KBT-1585 were noted.
5. The clinical usefulness rate of KBT-1585 was 73.4%.
These findings indicated that KBT-1585 was safe and effective antibiotic in skin and soft-tissue infections in surgery.

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Fundamental and clinical studies of lenampicillin (KBT-1585) in the surgical field were performed and following results were obtained.
1) Absorption and excretion
On three fasting patients with cboledocal T-tube drainage, serum and bile levels of ABPC were examined after oral administration of 500 mg of ABPC and the equivalent dose of KBT-1585, using a cross over method.
The peak serum levels in all cases after administration of KBT-1585 were two or three times higher than those of ABPC. And on 2 cases, the peak bile levels after administration of KBT-1585 were higher than those of ABPC.
2) Clinical results
KBT-1585 was administered to 19 patients with soft tissue infections and clinical results were excellent in 5 cases, good in 10 and fair in 4. The adverse reaction due to KBT-1585 was found in one case with eruption and itching.

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Lenampicillin (KBT-1585), a new prodrug of ampicillini, was investigated for its serum and bile concentration, clinical effectiveness and side effects.
Following an oral administration of 500 mg KBT-1585 to 2 patients (choledocholithiasis and cancer of pancreatic head), serum level reached the peak of 14.5 μg/ml after 2 hours in one case and 18.0 μg/ml after 3 hours in another case. Bile level reached the peak of 2.1 μg/ml 2-3 hours and 4.2 μg/ml 3-5 hours after administration respectively.
KBT-1585 was given to 77 patients with various surgical infection, mainly superficial soft tissue infections.
The clinical results were excellent in 11, good in 58, fair in 1, poor in 1 and efficacy rate was 89.6%.
No side effects were noted except for eruption in one case.

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Lenampicillin (KBT-1585), a newly developed oral pro-drug of ampicillin, was evaluated with respect to serum and bile concentration and clinical effect for patients with surgical infection. Following results were obtained.
Serum and bile levels of ABPC were evaluated on one patient with choledochal drainage. Serum drug level was 18.0μg/nil at the peak of 2 hours after oral administration of 500mg and in bile the levels were 11.0μg/ml at 2 hours and 20.5-21.0μg/ml at 4-5 hours after administration.
7 patients with surgical infection-2 cases of phlegmon, 1 of furuncle, 1 of felon and 2 of urinary truct infection. 4 strains of S.aureus from soft tissue infection and 1 strain of P. mirabilis from UTI were eradicated, and 1 strain of E. coli from UTI was decreased.
Clinical effects were good in 6 cases and fair in 1. Clinical effective rate was 85.7%.
No side effect was observed.

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Lenampicillin (KBT-1585), a new ampicillin ester for oral use, was administered to 24 patients with urinary tract infection and one patient with gonococcal urethritis at daily doses of 750 or 1, 500 mg for 3 to 15 days.
According to the criteria proposed by “the UTI committee”, the clinical efficacy of KBT-1585 was evaluated in 11 out of 13 female patients with acute simple cystitis and in all of 11 patients with complicated urinary tract infection, and the clinical efficacy rates were 90.9 % for both.
No side effect was observed, but in one patient, slight elevation of Al-P was noted.

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