A double blind study was carried out to compare the efficacy and safety of cefixime (CFIX), a new oral cephem with cefaclor (CCL) in the treatment of 245 children weighing 10-30 kg, with acute suppurative otitis media.
The daily dosages of CFIX and CCL were 3-6 mg/kg in 2 divided portions, and 20-40mg/kg in 3 divided portions, respectively, and the drugs were administered for 7 days.
The results obtained in this study are summarized as follows.
1. Analyzed subjects were 211 patients (CFIX group: 108 patients, CCL group: 103 patients) for clinical efficacy. Efficacy rates judged by the doctor in charge were 88.9% and 83.5% in CFIX and CCL group, respectively, without significant difference between the 2 groups. Similar results were also obtained by the committee.
2. When clinical effects were classified by clinical isolates, the efficacy rates against monomicrobial infections with Gram-negative bacteria were judged by the doctor in charge to be 100% in the CFIX group and 84.6% in the CCL group. Thus CFIX was judged to be significantly superior to CCL (P < 0.05).
3. The overall eradication rates of bacteria were 97.1% in the CFIX group and 90.3% in the CCL group. The eradication rate of CFIX was significantly superior to that of CCL (P < 0.05).
4. When improvements of individual symptoms were evaluated, regarding redness of the tympanic membrane and the tympanic cavity on the 3rd day of dosing, CFIX group (improvement in 84.1% of the cases) was significantly superior (P<0.05) to the CCL group (67.6%). Regarding purulent secretion on the 7th day of dosing, the CFIX group (improvementin 98.1% of the cases) was also significantly superior (P<0.05) to the CCL group (91.3%).
5. Two hundred thirty eight patients were analyzed for side effects (CFIX group: 120 patients, CCL group: 118 patients). The incidence rates of side effects were 0.8% (1/120) in the CFIX group and 1.7% (2/118) in the CCL group, and there was no significant difference between the 2 drugs. From the above results, it is concluded that CFIX is a useful oral antibiotic in the treatment of acute suppurative otitis media in chicken.
Furthermore, CFIX is expected to be equal or superior to CCL in clinical effects.

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The clinical efficacy and safety of cefixime (CFIX), a new oral cephalosporin, were com pared with those of cefroxadine (CXD) in patients sufferring from acute lacunar tonsillitis in a double blind study.
Two hundred and fifty two patients were given each orally 100mg of CFIX b.i.d. or 250 mg of CXD t.i.d. for, in principle, 7 days.
Number of patients evaluated for clinical efficacy was 202 (103 treated with CFIX and 99 treated with CXD). As for the backgrounds of patients, more severe cases were found in the CFIX group than in the CXD group (P< 0.01).
Efficacy rates evaluated by individual doctors were 88.3% in the CFIX group and 91.9% in the CXD group. There was no significant difference between the 2 groups.
Efficacy rates on the third day after the initiation of treatment evaluated by the committee were 40.8% in the CFIX group and 47.9% in the CXD group with no significant difference. Efficacy rate on the 7th day, however, was 79.8% in the CFIX group and 93.4% in the CXD group, showing a significant difference (P<0.05).
Bacteriological effectivenesses were satisfactory for both groups with eradication rates of 93.4% for the CFIX and 96.9% for the CXD group.
Number of patients evaluated for safety was 226 (110 treated with CFIX and 116 treated with CXD). No significant difference was observed between the 2 drug groups in incidences of side effects; gastrointestinal disturbances or rashes were noted in 6 patients (5.5%) of the CFIX group and in 5 patients (4.3%) of the CXD group. As for the abnormal laboratory findings, elevation of GOT & GPT was observed in 1 patient of the CFIX group.
From these results, it was concluded that 100 mg b.i.d. of CFIX was as useful as 250 mg t.i.d. of CXD in the treatment of acute lacunar tonsillitis.

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A clinical phase I study for T-2588 was carried out in 25 healthy male volunteers. Each volunteer received T-2588 in one of the following doses: 100 mg capsule or tablet as a single oral administration in fasting or non-fasting state, 200 or 400 mg capsule as a single oral administrationin non-fasting state or 300 or 600 mg daily for 14-15 days as a repeated administration in non-fasting state. The results are summarized below.
No subjective or objective adverse effects were noted after a single oral administration. But repeated dose of 300 mg daily for 15 days and 600 mg daily for 14 days brought about abdominal distension in 1 case and soft stool in 1 case, respectively.
As an abnormal change in clinical laboratory findings, 1 case with slight increase in transaminase after a single administration and 3 cases with slight increases in transaminase after repeated doses were observed.
Time to reach a maximum concentration of T-2525 in blood (T_max) was longer in subjects at non-fasting states than subjects in fasting states. Maximum blood concentration was lower in the latter than in the former. Urinary excretion rate in 8 hours after an oral administration was 19-28% and it was higher in non-fasting subject than in fasting subject. No accumulation of T-2588 was noted after repeated doses.

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Clinical efficiency and side effects of cefoperazone (CPZ) against 40 infectious diseases in the field of internal medicine were studied. In addition, relationship between clinical efficiency and the value of area under the time concentration curve (AUC) was evaluated.
1. It was possible to evaluate clinical responses in 36 cases of 40 infections; Responses were excellent in 15, good in 16, fair in 3 and poor in 2. An overall efficacy rate was 86.1%. A high dose of CPZ (2 g ×2/day) produced a higher efficacy rate than a low dose of the drug (1 g × 2/day) [95.8% (23/24 cases) vs. 66.7% (8/12 cases)] but the difference was not statistically significant.
2. It was possible to evaluate bacteriological efficacy in 32 cases. Bacteria were eradicated in 29 (90.6%) and decreased in 3
3. The value of AUC in the high dose group was significantly higher than that in the low dose group. Values of AUC in cases of excellent or good clinical responses tended to be higher than values in cases of fair or poor responses.
4. Side effects were noted in 4 cases, but they were not serious and improvements were observed without withdrawal of the drug except 1 case.

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Prophylactic effect of cefotaxime (CTX) against postoperative infection at a dose level of 2g intravenous per day for 5 days was investigated using fever index in patients who underwent abdominal cesarean section, abdominal simple panhysterectomy or radical hysterectomy. The results obtained are summarized as follows.
1. Total fever index values were 3.53±2.07 degree hours in a group receiving CTX for prophylactic purpose in abdominal cesarean section (n=15), 22.25±0.19 degree hours in a group that had infections before cesarean section and was treated with CTX (n=2), 3.79±3.87 degree hours in a group administered with CTX for prophylactic purpose in abdominal simple panhysterectomy (n=13), at a low level of 3.10±3.60 degree hours in a group administered with CTX and astromicin (400 mgi.m. per day for 5 days) for prophylaxis in abdominal simple panhysterectomy (n=13), and 6.72±3.14 degree hours in a group receiving CTX for prophylaxis in radical hysterectomy (n=7).
2. When daily fever index values were expressed as cumulative proportions (%) of total fever index, specific patterns were observed for different types of surgical procedures. As the results obtained in our current study as well as our previous study indicate, different antibiotics also influenced these patterns differently.
3. No abnormal laboratory findings nor side effects attributable to CTX were observed.

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Bacterial isolates from patients with pulmonary infections have been collected over the last 4 years in collaboration with investigators at 14 hospitals in various parts of Japan to study isolation frequency of pathogens from patients and drug susceptibilities of these isolates. Possible causative pathogens mainly isolated from sputum of patients with lower respiratory tract infections were collected during a period from September 1984 to March 1985.
We first determined types of respiratory diseases and found that, between 1981 and 1983, 57.9-64.5% of the examined diseases were chronic respiratory infections such as chronic bronchitis, chronic bronchiolitis and bronchiectasis, and that these infections including diffuse panbronchiolitis accounted for 63.1% in 1984. Bacterial pneumonia was found to be 24.8% in 1981, but it was 11.0% in 1983 and 15.1% in 1984. These results seemed to reflect decreases in the occurrence of bacterial pneumonia in young population.
We then investigated the correlations between these infections and isolates and found that distributions of causative organisms of chronic bronchitis and bronchievtasis during the 4 years were similar while the detection rate of Staphylococcus aureus from bacterial pneumonia increased in 1982 and 1983, and that of Gram-positive organisms such as Enterococcus faecalis rose in 1984.
Branhamella catarrhalis was considered to be a non-pathogenic organism normally harbored in the upper respiratory tract. Recently, however, respiratory infections caused by this organism have been reported by some investigators. In our research also, this Gram-negative diplococcus was isolated as a causative organism of respiratory infections as 6 strains were found in 1983 and 29 strains in 1984, hence an increase was observed.

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1. Pharmacokinetic study
Micronomicin (MCR) was administered by intravenous drip infusion at a dose of 180 mg to each of 3 advanced aged patients (average: 77 years). Peak serum concentrations ofthe drug reached levels ranging from 16.0 to 22.2 μg/ml (average 18.8±3.2 μg/ml). In 2 cases with normal renal functions, T 1/2 of MCR was 2.2-2.5 hours, whereas it was 4.3 hours in a case with a slight renal impairment. No accumulations nor adverse clinical reactions due to the drug occurred in treatment at a dose level of 360 mg daily for 5 days in each of the 2 patients. Also, no abnormal values were noted in β₂-MG, NAG, creatinine in blood and urine before or after the treatment in any of the above 3 patients.
2. Clinical study
The MCR was administered to 26 patients with chronic and complicated urinary tractinfections (CC-UTI). Twenty-four patients were treated each at a dose level between 240 and 360 mg daily for 5 days. Clinical efficacy was evaluated for 25 evaluable cases based on the UTI committee's criteria; excellent responses were observed in 4, moderate responses in 14 and poor responses in 7, thus, the rate of efficacy was 72%.
3. Safety
No side reactions were encountered nor clinical abnormal values observed in peripheral blood, in renal, liver functions.
4. Conclusion
The MCR was a highly e ffective and a safe drug in treatment of CC-UTI including cases of advanced aged patients at a dose in a range of 240-360 mg per day for 5 days administered by intravenous drip infusion. Appropriate dose levels, however, should be individually established for cases with renal impairment where the excretion of the drug may be retarded.

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Effects of isepamicin sulfate (HAPA-B), a new aminoglycoside antibiotic, on the neuromuscular transmission were studied in rats and compared with those of amikacin (AMK) or other aminoglycoside antibiotics.
The HAPA-B, as well as other aminoglycoside antibiotics, depressed the twitch response of diaphragm to phrenic nerve stimulation in vitro. The depression effects of different drugs were compared and graded in the order of strengths of blocking action as: netilmicin (NTL) > gentamicin (GM) > streptomycin (SM) > kanamycin (KM) > AMK > HAPA-B. The IC₅₀ (concentration which inhibited the response by 50%) of HAPA-B was 3.6 x 10^-3 g/ml. The neuromuscular blockade produced by HAPA-B was reversed by CaCl₂, KC1 or caffeine but not by neostigmine. D-Tubocurarine or MgCl₂. augmented the neuromuscular effects of HAPA-B. Intramuscular (400 mg/kg) and intravenous (100 mg/kg) injections of HAPA-B did not affect the twitch response of gastrocnemius muscle to sciatic nerve stimulation in situ. Intravenous injection of 200 mg/kg caused death in some rats and depression of the twitch response in others. Intravenous AMK produced no significant effect on the twitch response at 50 mg/kg and caused deathat 100 mg/kg. GM and SM caused death or significant degree of depression of the twitch response at intravenous doses of 50 mg/kg. In experiments of intravenous drug infusion for 60 minutes, the twitch response was depressed by HAPA-B at 400 mg/kg/hr and by AMK at 200 and 400 mg/kg/hr. In conclusion, HAPA-B has a neuromuscular blocking action presumably at the nerve terminal. However, its action was the weakest among the aminoglycoside antibiotics tested.

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General pharmacological properties of isepamicin sulfate (HAPA-B), a new aminoglycoside antibiotic, were studied in animals and the results obtained were summarized below.
1. Intramuscular injections of HAPA-B at doses of 500 mg/kg inhibited the writhing response induced by acetic acid, and at doses of 1,000 mg/kg, caused muscle relaxation, respiratory depression, supression of spontaneous motor activity and prolongation of thiopental anesthesia. Anticonvulsive action and the effect on the rectal temperature were not observed. Intravenous HAPA-B showed no significant effect on the general behavior and the function of the central nervous system at doses of 100 mg/kg.
2. Intravenous injections of HAPA-B to anesthetized dogs resulted increases in the femoral arterial blood flow at doses of 12.5 mg/kg, decrease in the blood pressure and increase in the respiratory rate at doses of 25 mg/kg, and increase in the carotid arterial blood flow at doses of 50 mg/kg. Apparent changes were not recognized in the heart rate and electrocardiograms. In conscious rabbits, intravenous HAPA-B produced increases in the heart rate without significant changes of the blood pressure and electrocardiograms at doses of 100 mg/kg. Spontaneous beatings of isolated atria were depressed by HAPA-B in concentrations of 3 ×10^-4 to 10^-8 g/ml.
3. The HAPA-B inhibited the gastric secretion at intramuscular doses of 500 mg/kg or intravenous doses of 100 mg/kg, and depressed charcoal transport through small intestine and the spontaneous movement of isolated ileum at intramuscular doses of 1,000 mg/kg and at concentrations of 3 ×10^-4 to 10^-8 g/ml, respectively. No irritative effect was found on the gastric mucousmembrane.
4. Inravenous HAPA-B inhibited the response of nictitating membrane to pre and post ganglionic stimulations of cervical sympathetic nerve at doses of 100 mg/kg. In in vitro test, HAPA-B inhibited nonspecifically the constrictive responses of trachea, aorta, stomach, ileum and was deferens to various agonists in concentrations of 3 ×10^-4 to 10^-8 g/ml.
5. Spontaneous movements of uteri of estrous or pregnant animals were depressed by HAPA-B at intravenous doses of 50 to 100 mg/kg and in in vitro at concentrations of 10^-4 to 3×10^-4 g/ml. Antidiuretic effect was also observed at intramuscular doses of 250 mg/kg.
6. HAPA-B increased the length of the whole blood clotting time and raised the plasma glucose level at intramuscular doses of 1,000 mg/kg and inhibited the platelet aggregation induced by ADP in in vitro at concentrations of 10^-8 g/ml. It showed neither effects on the collageninduced platelet aggregation and the recalcification time nor hemolytic effect in in vitro.
7. Intradermally injected HAPA-B increased the skin capillary permeability in concentrations of 0.1%.
8. These effects mentioned above were much the same as or somewhat slight than those of amikacin.

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Assay methods including microbiological assay (bioassay), high performance liquid chromatography (HPLC) and enzyme immunoassay (EIA) for isepamicin sulfate (HAPA-B), a new aminoglycoside antibiotic, in body fluids were studied.
The most suitable bioassay method was double layer agar-well method using Bacillus subtilis ATCC 6633 as the test organism on plate consisting of a seed-layer of nutrient agar at pH 8.0 and a base-layer of nutrient agar supplemented with 0.4% sodium chloride.
Sensitivities in bioassay, HPLC and EIA methods for plasma concentration were 0.08 μg/ml, 0.20 μg/ml and 0.05 μg/ml, respectively.
Plasma and urinary concentrations after intramuscular administration of HAPA-B at the dose of 200mg to healthy volunteers were measured with these 3 methods. The HPLC and the EIA methods yielded values which compared favorably to the bioassay method.
Using the bioassay method, HAPA-B levels in human plasma and urine samples were found to be stable at least for 15 days at-20°C.

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Absorption, distribution, metabolism and excretion of isepamicin sulfate (HAPA-B), a new aminoglycoside antibiotic, after a single administration were studied in rats.
After intramuscular administration of HAPA-B at a dose level between 6.25 and 100 mg/kg, the drug was rapidly absorbed to reach the peak in 0.10 to 0.21 hour (T_max.). The maximum drug concentration in the plasma (C_max) and the size of the area under the plasma concentration-time curve (AUC) depended on dose levels.
The HAPA-B disappeared rapidly from the plasma after intramuscular and intravenous administrationswith biological half-lives (T 1/2) from 0.41 to 0.47 hour with intramuscular administration and from 0.23 to 0.35 hour with intravenous administration.
Peak time after intramuscular, intraperitoneal and subcutaneous administration of HAPA-B at a dose of 25 mg/kg were 0.18, 0.24 and 0.37 hour, respectively. Maximum drug concentrations in plasma were 64.15, 53.71 and 40.39 μg/ml and biological half-lives of the drug were 0.47, 0.73 and 0.87 hour, respectively.
The HAPA-B was distributed rapidly into tissues, especially at a high level into kidney after intramuscular or intravenous administration of 25 mg/kg. Concentrations in lung and heart were next to that in kidney, but were not higher than plasma concentrations.
The drug was excreted mainly into the urine after intramuscular and intravenous administration within 24 hours and approximately 79 to 90% of the administered amount was excreted.
Meanwhile, the excretion of HAPA-B into the bile was 0.1% or less during the first 24 hours after intramuscular and intravenous administration.
Bioautograms of thin layer chromatographs of 0-6 hours urine samples after intramuscular administration showed single bands with the identical Rf value to the standard HAPA-B.
No difference between male and female was observed in the fate of the administered HAPAB through intramuscularly.
The shape of the plasma concentration curve and the urinary excretion after intramuscular administration of HAPA-B at the dose of 25 mg/kg was similar to those of amikacin (AMK) and gentamicin.
Tissue concentrations after intramuscular and intravenous administration of HAPA-B were also similar to AMK.

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The accumulation of isepamicin sulfate (HAPA-B) in tissues and plasma was studied upon multiple intramuscular and intravenous administrations of 25 mg/kg of HAPA-B daily for 8 or 15 days to male rats.
Shapes of plasma concentration curves in multiple intramuscular and intravenous administrations were very similar to that in a single administration.
Drug concentrations in kidney at 24 hours after 8-and 15-multiple administrations through both routes were 3 to 4 and 4 to 5 times as high as that after a single administration.
The concentration in kidney increased by multiple administrations for 8 days, but did not increase so highly there after till the 15-multiple administrations.
On the other hand, the elimination of HAPA-B from kidney after multiple administrations was similar to that after a single administration.
The accumulation of HAPA-B upon multiple administration was also observed in lung, heart, spleen and liver, but peak concentrations of the drug in these tissues were lower than that in kidney.

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Absorption, distribution, metabolism and excretion of isepamicin sulfate (HAPA-B) were studied following intramuscular, intravenous and drip intravenous administration at doses of 6.25, 25 and 100 mg/kg to rabbits.
Plasma concentrations of HAPA-B following intramuscular, intravenous and drip intravenous administration depended on dose levels. Biological half-lives (T1/2), body clearance (C1t) and areas under plasma concentration-time curves (AUC) for different routes of administration were similar in all 3 routes.
A theoretical curve for drug concentrations vs. time was obtained using pharmacokinetic parameters calculated from drug concentrations in plasma following a 45-minute drip intravenous administration. From the curve, it was estimated that 60 to 90 minutes would be required to achieve a similar maximum drug concentration in plasma by drip intravenous administration to that obtained by intramuscular administration. Thus, drug concentration patterns obtained following intramuscular administration could be duplicated in drip intravenous administration by regulating the length of time for infusion.
The concentration of HAPA-B in tissues obtained following a 15-minute drip intravenous administration reached maximum after 15 minutes at a level higher than that achieved by intramuscular administration, but an hour later, concentrations in tissues including the kidney decreased to similar levels obtained following intramuscular administration and patterns of concentration decrease for drip intravenous administration and intramuscular administration were quite similar to each other thereafter.
The drug was rapidly excreted into the urine following any of the 3 routes, and urinary recoveries in 24 hours were 75-92% of dose amounts for all dose levels tested.
Bioautograms on thin-layer chromatographs of 0-6 hours urine samples obtained following an intramuscular administration of the drug showed a single biologically active bands with similar Rf values to HAPA-B itself. No active metabolite of the drug was detected in the urine.

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The plasma concentration and urinary excretion of isepamicin sulfate (HAPA-B) were studied following intramuscular, intravenous and drip intravenous administrations of 6.25, 25 and 100mg/kg in dogs.
Maximum plasma concentrations (C_max) of HAPA-B after intramuscular, intravenous and drip intravenous administration depended on dosage levels. Biological half-lives (T1/2) and areas under plasma concentration-time curves (AUC) for the three different routes of administration were similar to each other.
The peak plasma concentration of HAPA-B achieved with intramuscular administration was similar to that with a 1-hour drip intravenous administration at a dose level of 6.25 or 25 mg/kg.
On the other hand, at a dose level of 100mg/kg, the C_max following intramuscular administration was similar to that following 2-hour drip intravenous administration. It was, therefore, presumed that the plasma concentration curves which are similar to that of intramuscular administration can be obtained by regulating the infusion time.
The observed C_max value for drip intravenous administration was a little higher than the theoretical C_max value for drip intravenous administration calculated from parameters for intramuscular administration. Simulation curves obtained for extended infusion times agreed more closely with observed curves than curves simulated for shorter infusion periods.
These investigations showed that plasma concentration curves for any dosage levels can be estimated from parameters calculated from experimental data obtained using intramuscular or drip intravenous administration.
HAPA-B was rapidly excreted into the urine after administration through any of these 3 routes and 71-89% of the dose was excreted into the urine in 24 hours at all dosage levels.
Bioautograms of thin-layer chromatographs of the 0-6 hours urine after intramuscular administration showed single bands with a similar Rf value to that of the standard HAPA-B.
No significant differences in plasma concentration and urinary excretion between HAPA-B and amikacin were observed upon intramuscular or intravenous administration of 25mg/kg.

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Plasma concentrations after a single or multiple intramuscular administrations of isepamicin sulfate (HAPA-B) at dose levels of 6.25, 25 and 100mg/kg to male and female dogs were measured by microbiological assay, and were also compared with those of amikacin at dose levels of 25 and 100mg/kg.
Shapes of plasma concentration curves after multiple administrations of HAPA-B were very similar to those after single administrations at all dosage levels tested.
On the other hand, the shape of plasma concentration curve after multiple administration ofamikacin at 100mg/kg was markedly different from that after a single administration.

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Absorption, distribution, metabolism and excretion of ¹⁴C-isepamicin sulfate (¹⁴C-HAPA-B) following a single intramuscular and intravenous administration of 25 mg/kg were studied in male rats.
1. After an intramuscular administration, the drug was rapidly absorbed and the maximum plasma level of about 75 μg/ml was obtained at 10 minutes after the administration. The plasma levels rapidly decreased following either intramuscular or intravenous route.
2. The HAPA-B was rapidly distributed into tissues except the central nervous system and the eye ball. Especially high concentrations were attained in kidney and cartilage tissues, concentrations in lung followed these tissues. Radioactivity remained in kidney for a long period, but it disappeared from cartilage and other tissues rapidly. The radioactivity in kidney was located in the cortex at 24 hours after administration.
There was no difference in the distribution of radioactivity with different administration routes.
3. The HAPA-B was mainly excreted in the urine following either intramuscular or intravenous administration. Approximately 80% of the dose by intramuscular and 92% by intravenous administrations were excreted during the first 4 hours. Within 24 hours, over 95% was recovered in either routes.
4. The radioautogram of the thin-layer chromatography of the 0-16-hour urine showed a single radioactive zone with an identical Rf value to HAPA-B.
5. Binding ratios of ¹⁴C-HAPA-B to plasma protein were less than 10% both in vitro and in vivo and to erythrocytes less than 9% in vitro.

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Tissue concentrations of ¹⁴C-isepamicin (¹⁴C-HAPA-B) and its excretion were studied in male rats after 8-and 15-successive intramuscular administrations of 25 mg/kg/day.
1. Plasma levels were hardly affected by the successive administration, and plasma con centrations as time patterns with 8-and 15-successive administrations were very similar to that with a single administration.
2.Kidney levels of the drug increased remarkably by successive administrations.
3.In all the organs tested except kidney, the elimination of the drug from the tissues tended to become somewhat slower with successive administrations but maximum concentrations were hardly affected by successive administrations.
4.There was little difference between the excretion rates (urinary and fecal) after the successive doses and that after a single dose.

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Placental transfer and excretion into milk of ¹⁴C-isepamicin sulfate (¹⁴C-HAPA-B) following a single intramuscular or intravenous dose of 25 mg/kg were studied in pregnant or lactating rats.
1. Concentrations of HAPA-B in placenta, ovary and uterus reached their maxima in 10 minutes after administration then declined rapidly. The maximum concentration in the fetal membrane was similar to 10-minute levels in these other tissues, but was attained in 4 hours or later after the drug administration and some drug still remained there even at 24 hours.
2. A small amount of radioactivity was distributed into the fetus and the maximum level in the fetus was attained in 1-4 hours after administration, much later than in maternal tissues.The concentration in the fetal kidney was the highest in the fetus, but only 1 μg/g or lower was found. A very small amount of radioactivity was also found in the fetal bone by radioautography.
3. The drug was excreted into milk at 2-4 tegiml during the first 6 hours and decreased a little in 24 hours after administration.
4. There was no difference in results due to administration routes.

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