Pharmacokinetic and clinical evaluations of micronomicin by intravenous drip infusion

The safety and pharmacokinetics of micronomicin (MCR) by intravenous drip infusion were evaluated and the intravenous drip infusion of MCR was carried out on several cases on which the blood levels and clinical usefulness of MCR were investigated. Five healthy adult male volunteers received by crossover method 1 hour intravenous drip infusion of MCR in doses of 60 and 120 mg and intramuscular injection in a dose of 120 mg. The mean highest serum level was 6.3 micrograms/ml by intravenous drip infusion of 60 mg, 10.7 micrograms/ml by intravenous drip infusion of 120 mg, and 10.3 micrograms/ml by intramuscular injection of 120 mg. Serum levels of MCR were similar for intravenous drip infusion and intramuscular injection of 120 mg of MCR. The biological serum half-lives of MCR were 2.15 hours by 1 hour intravenous drip infusion of 60 mg, 2.54 hours by 1 hour intravenous drip infusion of 120 mg, and 1.59 hours by intramuscular injection of 120 mg. The mean urinary recovery rates within 24 hours after administration were 74.3% by 1 hour intravenous drip infusion of 60 mg, 59.6% by 1 hour intravenous drip infusion of 120 mg, and 64.9% by intramuscular injection of 120 mg, the results being nearly consistent. In all treatment groups, MCR could be safely administered. Intravenous drip infusion of MCR in a dose of 60 or 120 mg once or twice a day was conducted on a total of 6 cases consisting of 2 cases of pneumonia and 4 cases of urinary tract infections.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic studies on micronomicin in dogs. Comparison of intramuscular and drip intravenous administration models

The pharmacokinetics of micronomicin (MCR) were studied in dogs after intramuscular (i.m.) and drip intravenous (d.i.v., 0.5, 1 and 2 hours) administration (10 mg/kg). After i.m. administration, the plasma levels of MCR followed a one-compartment open model, and after d.i.v. administration it followed a two-compartment open model. The peak plasma levels of MCR after i.m., 0.5, 1 and 2 hours d.i.v. administration were 28.7 +/- 6.5, 36.7 +/- 3.6, 30.2 +/- 5.1 and 20.3 +/- 2.3 mcg/ml, respectively. The pharmacokinetic parameters (T1/2, AUC, Kel, Vd and Cl) of MCR except Cmax and Tmax were not differentiated by the route of administration. Urinary recovery of MCR after d.i.v. administration was equal to that of MCR after i.m. administration.     

Pharmacokinetic studies of micronomicin using a continuous intravenous infusion method

The basic pharmacokinetics of micronomicin (MCR) were studied in 4 healthy adult volunteers. MCR 60 and 120 mg were intravenously administered in 30 and 60 minutes at constant rates by means of continuous infusion apparatus. The same dosages were also tested by intramuscular route. The concentrations of MCR in serum and urine were determined by HPLC and analyzed following the two-compartment open model after intravenous treatment and following the one-compartment open model after intramuscular treatment. When MCR was given by intramuscular route, the mean serum concentration of 4 subjects reached a peak of 3.98 micrograms/ml at 30 minutes after a dose of 60 mg and 6.7 micrograms/ml at 30 minutes after that of 120 mg. The peak concentration was achieved at the end of intravenous infusion and was dose-related, since it was 6.1 and 10.5 micrograms/ml after a 30-minute infusion of 60 and 120 mg, respectively, and 4.85 and 9.43 micrograms/ml after a 60-minute infusion of 60 and 120 mg, respectively. At 8 hours, concentrations dropped to less than 0.1 microgram/ml and to 0.2 microgram/ml or less after 60 and 120 mg, respectively, regardless of the route and rate of administration. The mean urinary recovery up to 8 hours ranged 84 to 92% of the dose. There were no appreciable differences in pharmacokinetic parameters among 4 modes of intravenous infusion, with a T1/2(beta) of 1.43 approximately 2.02 hours. In the case of intramuscular treatment, parameters analyzed following the one-compartment open model were on similar levels to corresponding values found after intravenous treatment and the T1/2 was 1.39 hours after 60 mg and 1.43 hours after 120 mg.(ABSTRACT TRUNCATED AT 250 WORDS)     

The pharmacokinetic studies on astromicin in dogs. Intramuscular, intravenous or drip intravenous administration

The pharmacokinetics of astromicin (ASTM), a new aminoglycoside antibiotics, was studied in dogs after intramuscular (i.m.), intravenous (i.v.) or drip intravenous (d.i.v.: for 0.5, 1 hr. or 2 hrs.) administration at a dose of 20 mg/kg. The pharmacokinetic parameters were calculated using one-compartment open model (i.m.) or two-compartment open model (i.v. and d.i.v.). The peak plasma levels of ASTM were 34.1 mcg/ml (i.m.), 50.5 mcg/ml (d.i.v., 0.5 hr.), 39.8 mcg/ml (d.i.v., 1 hr.) and 28.2 mcg/ml (d.i.v., 2 hrs.), respectively. The pharmacokinetic parameters (T1/2, AUC infinity, Kel, Vd and Cl) of ASTM except Cmax and Tmax were similar for different routes of administration. Urinary recovery rates of ASTM were 90.5% (i.m.), 95.2% (i.v.), 91.6% (d.i.v., 0.5 hr.), 92.6% (d.i.v., 1 hr.) and 93.5% (d.i.v., 2 hrs.) by 24 hours. After intramuscular, intravenous or 1 hour drip intravenous administration of ASTM, no active metabolite was found in urine of dogs.     

Studies on the metabolic fate of isepamicin sulfate (HAPA-B). III. Intramuscular, intravenous and drip intravenous administration of HAPA-B in rabbits

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 (Clt) 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 approximately 92% of dose amounts for all dose levels tested. Bioautograms on thin-layer chromatographs of 0 approximately 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.     

Studies on the metabolic fate of isepamicin sulfate (HAPA-B). IV. Intramuscular, intravenous and drip intravenous administration of HAPA-B in dogs

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 100 mg/kg in dogs. Maximum plasma concentrations (Cmax) 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 100 mg/kg, the Cmax 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 Cmax value for drip intravenous administration was a little higher than the theoretical Cmax 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 approximately 89% of the dose was excreted into the unrine in 24 hours at all dosage levels. Bioautograms of thin-layer chromatographs of the 0 approximately 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 25 mg/kg.     

The pharmacokinetic studies on astromicin in rats. Intramuscular, intravenous or drip intravenous administration

Absorption, tissue distribution and excretion of astromicin (ASTM) were studied in rats after intramuscular (i.m.), intravenous (i.v.) or drip intravenous (d.i.v.; for 15, 30 min. or 60 min.) administration at a dose of 20 mg/kg. The pharmacokinetic studies of ASTM were carried out using one-compartment open model (i.m.) or two-compartment open model (i.v. and d.i.v.). The peak values of ASTM observed in serum were 48.6 micrograms/ml (i.m.), 255.3 micrograms/ml (i.v.), 57.5 micrograms/ml (15 min. d.i.v.), 45.9 micrograms/ml (30 min. d.i.v.) and 39.1 micrograms/ml (60 min. d.i.v.). The pharmacokinetic parameters of ASTM after 15 min. d.i.v. administration were calculated as follows: Kel 0.110 min-1, T1/2 21.4 min., Vd beta 0.310 L/kg, Tmax 15.0 min., Cmax 58.6 micrograms/ml, AUC 1,991 micrograms X min/ml. ASTM was rapidly distributed into the kidneys and lungs. The peak values of ASTM in the kidneys were 156.8 micrograms/g (i.m.), 185.2 micrograms/g (i.v.), 132.9 micrograms/g (15 min. d.i.v.), 135.3 micrograms/g (30 min. d.i.v.) and 117.3 micrograms/g (60 min. d.i.v.). Urinary recovery rates of ASTM amounted to 85.5% (i.m.), 99.5% (i.v.) or 87.9% (30 min. d.i.v.). After i.m. or 30 min. d.i.v. administration of ASTM, no active metabolite was found in urine of rats.     

Clinical studies of intravenous drip infusion of micronomicin. 1. Absorption and excretion

Pharmacokinetics of MCR administered by 1 hour intravenous drip infusion were studied in healthy volunteers by two-compartment model. In 120 mg-dosage group (n = 3) studies were made by single administration, and in 60 mg-dosage group (n = 4) were administered twice daily and continued until a total of 9 doses. Results: When MCR was administered in a 60 mg dosage, its Cmax was 4.3 +/- 0.3 micrograms/ml (mean +/- S.D.) after the 1st dose and 3.7 +/- 0.4 micrograms/ml after the 9th dose, while it was 8.8 +/- 1.0 micrograms/ml when the dosage was 120 mg. It should be noted that in the case of repeated dosing with 60 mg, serum levels just before administration were always below the analytical limit. The mean of T 1/2 was 1.69 +/- 0.14 hours, remaining stable at all determination. The kinetic parameters that showed different values between determinations performed after the 1st and 9th 60 mg doses were V1 (0.107 vs 0.164 L/kg) and Kel (1.02 vs 0.68 hr-1). This was also the case with comparison of 2 different dosage groups (60 mg 1st vs 120 mg; V1: 0.107 vs 0.135 L/kg, Kel: 1.02 vs 0.72 hr-1). There was no evidence indicative of side effect of MCR. Discussion: The above results demonstrated that Cmax and other kinetic parameters were little influenced by whether MCR was administered by intravenous drip infusion or by intramuscular injection. There was a little larger difference in AUC between those 2 routes of administration but the differences seemed negligible when the same dosage was used. Pharmacokinetic studies are to be continued in subjects whose renal function is impaired in different ways to establish the optimum dosage regimen for MCR.     

A phase I study on intravenous drip infusion of astromicin

A phase I study on intravenous drip infusion of astromicin (ASTM, KW-1070), an aminoglycoside antibiotic, was performed on 9 healthy adult male volunteers to investigate the safety and pharmacokinetics of this drug. ASTM 200 mg was dissolved in 250 ml of saline and given to each of 6 volunteers by drip infusion in 1 hour. For comparison, 200 mg of ASTM in 1 ml of saline was injected intramuscularly. No subjective and objective reactions were found, and laboratory test value did not show any change possibly caused by ASTM. In a single administration study, Cmax was 10.8 micrograms/ml by intramuscular injection and 12.0 micrograms/ml by intravenous drip infusion. The areas under the time-serum concentration curve were 35.6 micrograms X hr/ml and 34.9 micrograms X hr/ml, respectively; that is, the serum levels of ASTM after one-hour intravenous drip infusion changed almost identically to those after intramuscular injection. In a multiple administration study, the change in serum levels of ASTM after the ninth administration was approximately the same as that after the first one. This means that no accumulation of ASTM in serum occurred. Recovery rates of ASTM in urine up to 8 hours after a single intramuscular injection and a single intravenous drip infusion were 85.4% and 87.5%, respectively. These results also support the conclusion that there is no accumulation of ASTM in the body by repeated administrations.     

Distribution and elimination kinetics of intravenously and intramusculary administered tobramycin in man.

The pharmacokinetic profile of Tobramycin, a new aminoglycoside antibiotic, has been determined in man following intravenous and intramuscular administration. The serum elimination of the antibiotic obeys two-compartment open model kinetics after intravenous injection. The fast (alpha) and slow (beta) disposition rate constants averaged 0.1169 min-1 and 0.0099 min-1 respectively. The volume of distribution at the steady-state averaged 0.123 liter kg-1 and the plasma clearance 0.8 ml min-1 kg-1. Calculation of the intrinsic absorption rate of an intramuscular dose according to the two-compartment open model indicates that absorption increases during the first 40 minutes, then decreases and is virtually complete 90 minutes after administration in all subjects. The absolute physiological availability of the intramuscular dose averaged 84.9%. A method of administration compatible with the kinetic properties of the drug is proposed.     

Comparison of dexamethasone pharmacokinetics in female rats after intravenous and intramuscular administration

This study seeks a route of drug administration that would produce a pharmacokinetic profile for dexamethasone not significantly different from the intravenous route in female rats and would offer reproducible drug input with minimal stress to the animals. The intramuscular (i.m.) route of drug administration vs intravenous (i.v.) injection were compared in three female Wistar rats administered 1 mg/kg dexamethasone phosphate. Dexamethasone plasma concentrations were measured by a normal phase HPLC assay for 12 h after drug administration. Dexamethasone exhibited monoexponential behavior after intravenous dosing and was absorbed rapidly after intramuscular dosing (absorption half-life of 14 min) with 86% bioavailability. Dexamethasone had a terminal half-life of 2.3 h after drug administration by either route. The volume of distribution of 0.78 l/kg and the clearance of 0.23 l/h/kg are in good agreement with reported pharmacokinetic parameters in male rats. Intravenous dosing can be replaced by intramuscular dosing without causing any marked difference in dexamethasone pharmacokinetics.     

Absorption, distribution, and excretion of arbekacin after intravenous and intramuscular administration in rats

Absorption, distribution, and excretion of arbekacin (HBK) were studied in rats after intravenous or intramuscular administration of HBK at a dose of 10 mg/kg or 20 mg/kg. Elimination half-lives of HBK were 0.69 hour for bolus intravenous administration, 0.55 hour for constant rate intravenous infusion, and 0.57 hour for intramuscular administration. Cumulative urinary excretions within 24 hours after administration were 74.7% of the dose for bolus intravenous administration, and 79.1% of the dose for intramuscular administration. No significant difference was observed in the cumulative urinary excretions between the 2 administration routes. Cumulative biliary excretions within 24 hours after administration were around 0.1% of doses regardless administration routes, bolus intravenous or intramuscular administration. The tissue or organ distribution of HBK after bolus intravenous administration was similar to that after intramuscular administration. The drug was distributed most abundantly into the kidney followed by plasma and the lung. The distribution of the drug into the liver was the least among the 6 tissues or organs examined in this study. The protein binding of HBK was studied by an equilibrium dialysis method at three different concentrations of HBK, 5, 10, and 20 micrograms/ml. Binding ratios of HBK to human serum, human serum albumin, and rat serum were less than 15%.     

Pharmacokinetics in neonates and infants following administration of amikacin

Sixteen neonates (at ages of 8 to 28 days) and 8 infants (at ages of 35 days to 1 year), who were in need of treatment with amikacin sulfate, were subjected to the present study. The drug was administered by intramuscular route (1.39 to 3.13 mg/kg) or by intravenous drip infusion over a 30 to 60 minutes period (2.94 to 6.00 mg/kg). Blood levels and urinary excretion of the drug were investigated with these subjects. The blood levels were also analyzed according to pharmacokinetic models. 1. When the drug was administered intramuscularly to neonates at average doses of 1.49 and 2.96 mg/kg and to infants at average doses of 2.97 mg/kg peak levels of 2.74, 6.53 and 8.55 micrograms/ml, respectively, were attained at 30 minutes after dosing. 2. When the drug was administered to neonates at average doses of 3.01 and 5.89 mg/kg by intravenous drip infusion over a 30 to 60 minutes period and to infants at average doses of 2.97 and 6.00 mg/kg in the same manner, peak levels of 7.70, 20.9, 9.40 and 23.0 micrograms/ml, respectively, were attained at the end of the intravenous drip infusion. 3. Urinary levels and recovery rates tended to increase with ages of these subjects. Urinary recovery rates for the neonates and the infants were 41.0 and 58.9%, respectively, on the average. 4. From a pharmacokinetic analysis of blood levels of the drug, it was concluded that, in any of the subjects who received the drug intramuscularly or by intravenous drip infusion, it would be possible to use the one-compartment open model. In the subjects who received the drug by intravenous drip infusion, however, it was determined the two-compartment open model would be the choice. 5. In the neonates and the infants, whose blood levels were analyzed according to the one-compartment open model, Ka values averaged 7.51 and 6.62 hr-1, respectively, with respective average Kel values of 0.32 and 0.66 hr-1. Average Vd values obtained were 0.36 and 0.26 L/kg, respectively. There was a negative correlation between the Vd values and the ages of the subjects, while there was a positive correlation between the Kel values and the ages. 6. Appropriate conditions for administering the drug by intravenous drip infusion to neonates and infants at ages of more than 1 week were investigated taking observed blood levels and achieved peak levels and trough levels calculated using the one-compartment open model into account.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clinical studies of intravenous drip infusion of micronomicin. 1. Pharmacokinetics (Part 2). Intravenous Micronomicin Research Group

Following the previous report on pharmacokinetics of micronomicin (MCR) in healthy volunteers, pharmacokinetic studies were made again in patients with different degree of renal impairment, and a nomogram was obtained. MCR at a dose of 60 mg/time was given by 1-hour drip infusion to 14 inpatients who consented to receive MCR (age: 35 to 84 years, Ccr: 17.96 to 104.35 ml/min). The blood collection was performed in accordance with the schedule made upon the degree of renal impairment, and the serum concentration was determined by HPLC method. The results were analyzed by MULT program using two- or one-compartment open model. The serum concentration (Cmax) just after administration of MCR was 5.8 +/- 0.9 microgram/ml (mean +/- S.D.). The biological half-life was 1.81 to 12.35 hours. Taking the above results into consideration together with the previous ones of healthy males, the following correlation was obtained between the elimination constant (Kel or beta) and Ccr calculated from S-Cr.: Kel or beta = 0.0038 X Ccr - 0.0097. Further, no side effect was observed in these studies. Elimination of MCR from blood was dependent on renal function like other aminoglycosides, and so it was possible to estimate the elimination constant from Ccr. From these results, a nomogram for the optimum dosage regimen of MCR was obtained.     

Pharmacokinetics of ceftizoxime suppository in experimental animals

Ceftizoxime suppository (CZX-S) was administered rectally to mice, rats and dogs, and the pharmacokinetics were studied in comparison with those after intravenous, intramuscular and subcutaneous administration of ceftizoxime (CZX). Absorption of CZX given rectally was rapid in all animals, similar to intramuscular or subcutaneous administration. The peak serum levels of CZX in mice, rats and dogs when administered rectally at a dose of 25 mg/kg were 23.1 micrograms/ml at 7.5 minutes, 23.5 micrograms/ml at 15 minutes and 25.2 micrograms/ml at 15 minutes, respectively. These values were about 76%, 68% and 42% of the values for subcutaneous or intramuscular administration in mice, rats and dogs at the same respective doses. Urinary recoveries of CZX after rectal administration of 25 mg/kg were 44.2% (0-12 12 hours) in rats and 27.7% (0-6 hours) in dogs, and 2.7% (0-6 hours) of the dose was excreted into bile fluid in rats. Organ distribution of CZX when administered rectally to rats was similar in distribution pattern to that of muscular administration, although its concentrations in various organs were slightly lower than those for intramuscular administration, as was the case for serum concentration. Serum concentrations of CZX were proportionately elevated with dose when dogs were rectally administered CZX-S in doses of 12.5, 25 and 50 mg/kg. In the case of multiple administrations (t.i.d. for 10 days) of CZX-S to dogs, no remarkable difference was found in serum concentrations of CZX in comparison with single doses, and no accumulation of CZX was demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)     

金银花提取物中绿原酸在大鼠体内药动学和生物利用度的研究

目的:研究金银花提取物经不同途径给药后绿原酸在大鼠体内的药动学和绝对生物利用度。方法:建立大鼠血浆中绿原酸的HPLC-MC/MC检测方法。考察大鼠分别经静脉注射(iv)、肌内注射(im)及灌胃(ig)给药后血药浓度变化。用WINNONLIN 6.1软件计算药动学参数,根据药-时曲线下面积AUC_0-∞和给药剂量计算肌注和灌胃金银花提取物中绿原酸的绝对生物利用度。结果:大鼠经静脉注射、肌内注射和灌胃金银花提取物后,绿原酸在大鼠体内代谢过程均符合二室模型,消除半衰期分别为(0.44±0.08)、(0.50±0.12)、(0.38±0.11)h;AUC_0-∞分别为(6931.62±1528.35)、(6550.34±1025.41)、(2591.87±784.21) μg·h·L^-1。灌胃和肌注金银花提取物后其绿原酸的绝对生物利用度分别为37.39%和94.50%。结论:肌内注射与静脉注射金银花提取物在大鼠体内的药动学过程类似,肌注给药的生物利用度较高,灌胃生物利用度低,该结果可以为金银花提取物的给药途径和剂型研究提供科学依据。     

Studies on the metabolic fate of isepamicin sulfate (HAPA-B). I. Absorption, distribution, metabolism and excretion in rats

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 (Tmax). The maximum drug concentration in the plasma (Cmax) 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 administrations with biological half-lives (T1/2) 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 micrograms/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 approximately 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 HAPA-B 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.     

Clinical study on intravenous infusion of micronomicin

In recent years, aminoglycoside agents as well as beta-lactam antibiotics have been increasingly used with increased incidence of opportunistic infection caused mainly by Gram-negative bacteria. Therefore, we administered micronomicin sulfate (MCR), reportedly lower in nephrotoxicity, at doses of 60 and 120 mg by intravenous drip infusion for 1 and 2 hours to healthy male volunteers and determined the blood level and the urinary recovery rate. The peak of blood level after 1 hour infusion of MCR was 7.3 micrograms/ml in the 60 mg group and 9.5 micrograms/ml in the 120 mg group. T 1/2 (beta) was 3.34 and 2.48 hours respectively. The peak of blood level after 2 hours infusion of MCR was 5.7 micrograms/ml in the 60 mg group and 8.7 micrograms/ml in the 120 mg group. T 1/2 (beta) was 3.36 and 3.71 hours respectively. In the 120 mg group, the urinary recovery rate for the first 24 hours was 53.5% after 1 hour infusion and 60.9% after 2 hours infusion. In the 60 mg group, the rate was higher, 90.1 and 98.6% respectively. It was suggested that intravenous drip infusion of 120 mg of MCR for 1 hour is comparable to intramuscular injection of the same dose. Further, safety and effectiveness of this drug were studied in 7 clinical cases of urological infection. Good results were obtained in 7 clinical cases given 60 or 120 mg of MCR by intravenous drip infusion. Neither side effects nor abnormal laboratory findings were observed in clinical cases.     

Studies on the intravenous administration of amikacin to neonates

Amikacin (AMK) was administered mainly to neonates by either intravenous drip infusion or intramuscular injection and its pharmacokinetic changes were investigated. The results obtained are summarized as follows. 1. Serum half-lives of AMK in neonates at ages 0 to 3 days were longer than those at ages 4 to 10 days. Serum half-lives were prolonged particularly in neonates at an age 0 day. Neonates at ages 11 to 15 days, also showed longer half-lives in comparison to infants. Similar peak serum levels were observed in all the neonates with ages 0-15 days. 2. Similar serum AMK levels were obtained in neonates through intravenous drip infusion and through intramuscular injection at a same dose level. 3. When the drug was administered to neonates at 3.0 to 6.0 mg/kg by intravenous drip infusion, peak serum levels did not reach 30 micrograms/ml which is considered to be the critical level for AMK to be toxic. 4. Urinary excretion rates in neonates 11 day or older were almost the same levels as in infants. 5. AMK, when administered through intravenous drip infusion, was observed to have a higher migration rate to saliva when compared with kanamycin administered through intramuscular injection. 6. Based on the results obtained from the present study, the following doses seem to be optimal for neonates, but further studies are required to be conclusive. For neonates: 2.0 to 5.0 mg/kg daily in 1 to 2 divided doses. (For those at ages of 0 to 3 days: 2.0 to 3.0 mg/kg) For infants: 3.0 to 8.0 mg/kg daily in 1 to 2 divided doses through intravenous drip infusion over a period of 30 minutes to 1 hour.     

Safety and pharmacology of aspoxicillin in healthy volunteers

Aspoxicillin (ASPC), a new injectable semisynthetic penicillin, was administered to healthy volunteers to elucidate its safety and pharmacokinetics. No abnormalities obviously attributable to ASPC were observed in the examinations covering subjective and objective symptoms, blood pressure, heart rate, respiratory rate, electrocardiogram and body temperature, as well as in hematology, blood chemistry and urinalysis. There were slight increase in LDH (1 case), Al-P (1 case) and blood-glucose levels (2 cases) at 2 or 4 weeks after the administration with intravenous bolus consecutive injection (1 g X 1 or 2/day, 8 to 10 times), but these increases were not considered to be attributable to ASPC. When ASPC was administered by consecutive intravenous bolus injection, there observed no tendency of accumulation of the drug in serum or urine. When 1 g of ASPC was given intramuscular (i.m.), intravenous injection (i.v.) and intravenous drip infusion (d.i.) route, the maximum antibiotic levels in serum reached 25.2 micrograms/ml, 118.2 micrograms/ml and 70.3 micrograms/ml at 0.75 hour, 0.08 hour and 1 hour after the administration, respectively. The biological half-lives of ASPC attained by these 3 different routes were as follows: 1.73 hours (i.m.), 1.65 hours (i.v.) and 1.44 hours (d.i.). In a cross-over test with piperacillin (PIPC), serum levels of ASPC were higher than those of PIPC and half-lives of ASPC were longer. The 8 hours urinary recovery of ASPC was 75.9% after intravenous injection, 74.6% after intramuscular injection and 88.0% after intravenous drip infusion. Most of urinary recovery was excreted within 4 hours after administration regardless of dose levels, frequency of dosing or administration route. Thin layer chromatographic bioautography was conducted with the samples of serum and urine collected from subjects received ASPC. No antibacterial metabolite was observed in the serum obtained 2 hours after administration but a metabolite identified as amoxicillin was detected in a part of urine samples collected after 8 to 10 hours after the injection.