The pharmacokinetics and serum and urine bactericidal activity of ciprofloxacin

Ciprofloxacin is an investigational quinolone agent possessing an impressive antibacterial spectrum. Its pharmacokinetics were studied in six volunteers after 250-mg and 500-mg single oral doses, and its bactericidal activity compared to that of trimethoprim-sulfamethoxazole given to the same volunteers. Mean peak serum levels were 1.45 micrograms/mL and 2.46 micrograms/mL for 250-mg and 500-mg doses, and time to peak was 1 and 1.3 hours. The 12-hour levels were 0.12 micrograms and 0.22 microgram. Half-life (T1/2)alpha were 0.32 and 0.43 with T1/2 beta were 3.97 and 4.15 and volume of distribution (area) were 80L and 90L, respectively. Area under the concentration curve (AUC) was 5.65 h X micrograms/mL and 10.37h X micrograms/mL. Serum clearance was 23L for both doses. Approximately 49% of the 250-mg dose and 43% of the 500-mg dose was recovered in the urine. Bactericidal levels were determined against clinical isolates. Sera at 1.5 hours after the 500-mg dose averaged bactericidal levels of 1:20 or better for an Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and beta-lactamase producing Haemophilus influenzae and Branhamella catarrhalis. Urinary bactericidal levels at eight to 12 hours were greater than or equal to 1:157 for E coli, K pneumoniae, gentamicin-piperacillin resistant P aeruginosa, Staphylococcus aureus, and 1:20 for Streptococcus faecalis. Serum bactericidal levels were superior, and urine bactericidal levels were superior or equal to the bactericidal levels obtained with trimethoprim-sulfamethoxazole.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of cefatrizine after oral administration in human volunteers

The oral bioavailability of cefatrizine was studied in four groups, each of ten healthy young male volunteers. Capsules and suspension formulations were each administered at doses of 250 and 500 mg. Both the capsules and suspensions had mean peak plasma levels at 1.6 h at both dose levels. Mean peak plasma levels were 4.1 and 4.3 micrograms/ml for the 250 mg capsule and suspension doses respectively and 7.1 and 7.5 micrograms/ml for the 500 mg capsules and suspension doses respectively. The overall mean half-life was 1.7 h. For both types of formulations and at both dose levels 63-65% of the doses were excreted in the urine as intact cefatrizine, 85% of this amount within 8 h. The overall mean renal clearance was 157 ml/min. The cefatrizine capsule and suspension formulations were completely bioequivalent in regard to both rate and extent of bioavailability. Plasma concentrations and urinary recoveries of cefatrizine were higher than those previously reported, due to precautions taken in sample collection and storage.     

Clinical studies on the effect of imipenem/cilastatin sodium on infections in obstetrics and gynecology. Tissue concentrations and clinical effects

Tissue transfer and clinical effects of imipenem/cilastatin sodium (MK-0787/MK-0791), a new carbapenem antibiotic, were studied and the following results were obtained. Penetrations of MK-0787 into uterine arterial blood and into pelvic dead space exudate were good. When MK-0787/MK-0791 was administered at a dose of 500 mg/500 mg by a 30-minute intravenous drip infusion, the peak level of MK-0787 in uterine arterial blood was 22.2 micrograms/ml, 30 minutes after the completion of the drip infusion. The peak level of MK-0787 in pelvic dead space exudate was 12.9 micrograms/ml at 2 hours and it dropped to 2.6 micrograms/ml at 6 hours. MK-0791 levels were similar to those of MK-0787. Penetrations of MK-0787 into tissues were also good. When MK-0787/MK-0791 was administered at a dose of 500 mg/500 mg by a 30-minute intravenous drip infusion, the level of MK-0787 was 2.2 +/- 1.1 micrograms/g in the oviduct, 2.7 +/- 2.1 micrograms/g in the ovary, 2.5 +/- 1.2 micrograms/g in the endometrium, 3.0 +/- 1.6 micrograms/g in the myometrium, 3.1 +/- 1.9 micrograms/g in the cervix uteri and 3.8 +/- 2.0 micrograms/g in the portio vaginalis at 1 hour after administration. These levels were reduced to halves, respectively, in approximately 2 hours. Four patients with intrauterine infections and 2 with vaginal stump infections were treated with MK-0787/MK-0791 at a daily dose of 1 g/1 g (500 mg/500 mg X 2). Good clinical and bacteriological responses were observed in 5 patients and causative organisms were eradicated in 2 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical study on imipenem/cilastatin sodium in the field of pediatrics

Imipenem/cilastatin sodium (MK-0787/MK-0791) was administered to pediatric patients with infections, and the following results were obtained. Pharmacokinetic study Two children, 11 years of age (38 kg body weight) and 3 years of age (15.5 kg body weight), were administered by 30 minutes intravenous drip infusion a single dose of 500 mg/500 mg (13.2 mg/13.2 mg per kg) and 250 mg/250 mg (16.1 mg/16.1 mg per kg) of MK-0787/MK-0791, respectively. Serum concentrations of MK-0787 reached their peaks at the end of drip infusion at a value of 56.33 micrograms/ml and 55.98 micrograms/ml, respectively. Concentrations of the drug decreased as the time after the administration increased, and they reached 0.14 microgram/ml and 0.12 microgram/ml, respectively in the older and the younger children at 6 hours after the administration. Half-lives (T 1/2) of the drug in serum were calculated to be 1.21 hours and 1.04 hours, respectively. The concentration of the drug in cerebrospinal fluid for the 11 years old was 0.52 microgram/ml 2 hours after the drip infusion and the serum concentration at the time was 4.02 micrograms/ml. Peak serum concentrations of MK-0791 in the 2 children were 53.73 micrograms/ml and 22.99 micrograms/ml, respectively, at the end of drip infusion. After 1 hour, the serum concentration of the drug decreased to 10.54 micrograms/ml in 1 case and not detectable in the other case. Urinary recovery rates of MK-0787 in 6 hours after the drip infusion was 82.9% and 63.6% in the 2 children and those of MK-0791 were 57.9% and 74.6%. Clinical study Clinical studies on MK-0787/MK-0791 were carried out in 6 pediatric patients; 1 each with femoral cellulitis, sepsis suspected, salmonellosis, acute tonsillitis, bronchopneumonia and streptococcosis. Lengths of treatment were 2 2/3-4 days for 5 cases and 6 days for 1 case. The patients were treated by 30-60 minutes intravenous drip infusions twice a day for 1 case, and 3 times a day for 5 cases at daily doses of 54.5-66.7 mg/kg. The treatment was effective in all cases, with 3 cases judged excellent and 3 cases good. The safety of the drug was studied in 7 patients. No side effects nor clinically abnormal values were observed in any cases.     

Human intravenous and intramuscular pharmacokinetics of amoxicillin

Amoxicillin was administered at doses of 500 mg and 1000 mg, intravenously and intramuscularly to normal volunteers in a parallel study. Intramuscular amoxicillin was 100% bioavailable at both dose levels. Mean peak serum levels observed for the 500 mg and 1000 mg doses, respectively, were: i.v. (5 min after dosing) 46 and 74 micrograms/ml; i.m. (30 min after dosing) 14 and 21 micrograms/ml. Six hour trough levels ranged between 0.5 and 0.9 micrograms/ml. Between 50% and 60% of the doses were excreted in urine as intact amoxicillin in the 24 h after dosing. Almost 90% of this excretion occurred in the first 3 h after dosing. There was a statistically significant increase in mean clearance, after i.v. dosing, from the 500 mg level (14.8 l/h) to the 1000 mg level (20.7 l/h) implying that amoxicillin pharmacokinetics are non-linear over this range. Since there was very little difference between mean renal clearances at these dose levels (9.2 and 11.7 l/h, respectively) this clearance change might be due to enhancement of non-renal clearance. It would not be expected that this non-linearity would have any therapeutic influence.     

Comparative pharmacokinetic profiles of cinoxacin and pipemidic acid in humans

Serum and urinary levels of Cinoxacin and pipemidic acid were determined at 7-day intervals in the same 10 healthy volunteers after a single oral dose of respectively 500 and 400 mg of the drugs. Comparison of results shows that Cinoxacin was absorbed faster (absorption half-life, ta 1/2cin = 0.25 h) than pipemidic acid (ta 1/2pip = 0.37 h) and distributed in a smaller apparent volume (AVDcin = 23.5 1/1.73 m2; AVDpip = 60.1 1/1.73 m2). Biological half-lives were identical (tb 1/2cin = 2.10 h; tb 1/2pip = 2.15 h). On the other hand, serum levels for Cinoxacin at 1, 2 and 4 hours (8.1 +/- 1.5 micrograms/ml, 10.6 +/- 1.5 micrograms/ml, 5.6 +/- 1.3 micrograms/ml respectively) were higher than those for pipemidic acid (3.3 +/- 0.3 micrograms/ml, 3.4 +/- 0.5 micrograms/ml, 2.1 +/- 0.5 micrograms/ml respectively). Urinary excretion of the two derivatives during the 12 hours following their administration was similar (Ucin0-12h = 86%; Upip0-12h = 83%). Mean urinary concentrations were particularly high, still attaining respectively 90 +/- 29 micrograms/ml and 131 +/- 38 micrograms/ml in samples collected between the 9th and the 12th hours; these levels were well above the M.I.C. for the Gram-negative organisms included within the spectrum of activity of these two quinolones. In addition, predictive calculations of serum levels reached after multiple dosing indicate that at an administration rate of 500 mg every 6 or preferably every 4 hours, Cinoxacin concentrations should be sufficiently high to be of interest in the treatment of systemic infections by sensitive organisms.     

Chlormezanone plasma and blood levels in patients after single and repeated oral doses and after suicidal drug overdose

Chlormezanone plasma concentrations were determined in 5 volunteers (group 1) after a single oral dose of 200 mg of chlormezanone with high performance liquid chromatography. A plasma elimination half-life of 23 +/- 2.3 h was calculated. The mean peak chlormezanone plasma level was 1.86 +/- 0.2 micrograms/ml, 1 h after ingestion. Additionally, chlormezanone plasma levels were determined after repeated oral doses of chlormezanone recommended for treatment of muscular spasms due to degenerative skeletal disease. After 5 days of repeated daily doses of 3 x 200 mg (group 2; 12 patients) or 3 x 400 mg (group 3; 10 patients) of chlormezanone, mean predose chlormezanone plasma levels were 12.0 +/- 2.0 micrograms/ml (group 2) and 22.7 +/- 4.0 micrograms/ml (group 3), respectively. Comparable plasma concentrations were determined after 10 days of repeated doses of 3 x 200 mg or 3 x 400 mg of chlormezanone in 3 patients from each of these 2 groups. In 7 patients of group 3, chlormezanone had to be discontinued on the 5th day due to increasing muscular weakness, ataxia and exercise-inducible tachycardia. After a loading dose of 800 mg and repeated doses of 3 x 200 mg chlormezanone to 5 patients (group 4), plasma levels of 6.5 +/- 2.1 micrograms/ml, 8.9 +/- 2.2 micrograms/ml, 12.7 +/- 2.0 micrograms/ml, and 10.4 +/- 2.4 micrograms/ml were determined after 2, 8, 16, and 36 h, respectively. Trace amounts of a degradation product of the acid-labile chlormezanone could be detected in plasma besides the unchanged drug after administration of repeated oral doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical evaluation of ceftazidime in paediatrics

Ceftazidime ( CAZ ), a new injectable cephem antibiotic, was used for treatment of infections in children, and the following results were obtained. After an intravenous injection of CAZ at a dose of 20 mg/kg, the mean blood levels in 2 patients were 41.5 micrograms/ml at 30 minutes, 18.1 micrograms/ml at 2 hours and 2.55 micrograms/ml at 6 hours, with the half-life (T 1/2) of 1.37 hours. In a 22-day-old baby with meningitis given CAZ intravenously at a dose of 43.5 mg/kg, the blood levels were 100 micrograms/ml at 30 minutes, 68 micrograms/ml at 2 hours and 25 micrograms/ml at 6 hours, with the half-life (T 1/2) of 2.96 hours. After intravenous administration of CAZ in doses ranging from 35.7 to 50 mg/kg, CSF concentrations ranged from N.D. to 6.3 micrograms/ml in 3 patients with purulent meningitis, although 19 micrograms/ml at 1 hour and 13 micrograms/ml at 2 hours in 1 patient after intravenous administration of 46.7 mg/kg. In patient with mumps meningitis, CSF concentrations were undetectable after intravenous administration of 35.7 mg/kg. Seventeen patients (each 1 patient with lymphadenitis, tonsillitis and septicemia, each 2 patients with pneumonia, bronchiectatic bronchitis, pyothorax and purulent meningitis, each 3 patients with pyelonephritis and enteritis) were treated with CAZ intravenously, at the daily doses of 178.2 mg/kg and 200 mg/kg in 4 divided doses in patients with meningitis and 44.1 to 103.4 mg/kg in 3 divided doses in patients with other infections (two of them were given by intravenous drip infusion for 30 minutes). The clinical responses were excellent or good in all the patients except for 1 case of Salmonella enteritis (poor) and 1 case of Campylobacter enteritis (poor). The efficacy rate was 88.2%. It was noteworthy that the clinical response was excellent in 1 case of septicemia with P. aeruginosa with leukemic stage of malignant lymphoma and in 2 cases of purulent meningitis. As side effects, fever, eruption, leukocytopenia, elevation in GOT and positive CRP considered to be allergic, were observed on day 16 of administration in 1 case of pyothorax. These symptoms disappeared by discontinuance of administration. In addition, there were elevation in GOT and GPT in 2 cases and elevation in GOT in 2 cases and elevation in GPT in 1 case; they were all mild or transient, and there was nothing to be worried about.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clinical evaluation for T-1982 (cefbuperazone) in the field of pediatric infection

T-1982 (cefbuperazone), a new injectable cephamycin antibiotic, was employed for bacterial infections in children, and the following results were obtained. 1. When administered intravenously at a dose of 20 mg/kg to a 6-year-old female child, serum levels were 62 micrograms/ml at 30 minutes, 39 micrograms/ml at 1 hour, 17.6 micrograms/ml at 2 hours, 6.8 micrograms/ml at 4 hours and 2.9 micrograms/ml at 6 hours with serum half-life (T 1/2) of 76 minutes. Urinary excretion rates were 41.0, 5.3% and 2.4% respectively at 0-2, 2-4 hours and 4-6 hours, and urinary levels were 820 micrograms/ml, 182 micrograms/ml and 310 micrograms/ml, respectively. The total urinary recovery within 6 hours was 48.7%. 2. A total of 11 cases of pediatric infections was treated with T-1982. The clinical efficacy evaluated for 9 cases, excluding 2 cases of non-bacterial infections, was as follows; excellent in 4, good in 1 out of 5 cases of pneumonia, good in 1 case of cervical purulent lymphadenitis, and excellent in 1, good in 1, poor in 1 out of 3 cases of urinary tract infection. 3. As side effect, mild diarrhea in 1 case and slight elevation of GOT, GPT in 2 cases were observed. 4. These results suggest that T-1982 is of good use for bacterial infections in children and the expected efficacy is obtained at a dose of 20 mg/kg 3 times a day.     

A pharmacokinetic investigation of sisomicin administered intramuscularly to children

For the purpose of studying the pharmacokinetic profile of sisomicin (SISO) and the proper conditions for its administration to children, SISO was administered intramuscularly to 10 infants aged less than 1 year, 16 young children and 18 school children at doses of 1.0, 1.5 and 2.0 mg/kg and its serum and urine levels were determined by bioassay. The mean peak levels of SISO in serum appeared at 1/4 hour in the infants, irrespective of the dose; the mean peak levels were 2.27, 3.05 and 4.83 micrograms/ml after the 1.0, 1.5 and 2.0 mg/kg doses, respectively. In the young children, the mean peak levels appeared at 1/4 hour after the 1.0 mg/kg dose and at 1/2 hour after both the 1.5 mg/kg and 2.0 mg/kg doses. The mean peak levels were 2.82, 3.80 and 6.43 micrograms/ml, respectively. In the school children, the mean peak levels appeared at 1/2 hour after all the doses and were 4.34, 5.31 and 6.87 micrograms/ml, respectively. The mean peak levels were in the order of school children greater than young children greater than infants and were dose-dependent. In the infants, the mean urinary recovery was 43.7% for the 1.0 mg/kg dose and 31.2% for the 1.5 mg/kg dose; in the young children, 50.5, 35.9 and 65.6% for the 1.0, 1.5 and 2.0 mg/kg doses, respectively; and in the school children, 54.2, 50.2 and 56.7%. Using the observed serum levels, the pharmacokinetic parameters were calculated according to the one-compartment open model theory. (1) The mean elimination rate constants (K) were calculated at 0.60, 0.67 and 0.56 hr-1 for the infants, young children and school children, respectively. There were found no great differences among the above 3 age groups. The mean absorption rate constants (ka) were 18.5, 7.6 and 5.9 hr-1 and the apparent volumes of distribution per kg body weight, Vd (L/kg), 0.44, 0.26 and 0.22 L/kg, respectively. These 2 parameters were significantly greater in the infants than in the young children and school children. The maximum serum concentration (Cmax) and the time when the concentration reaches a maximum (Tmax) were substantially in agreement with the observed values. The half-lives (T1/2) were 1.16, 1.03 and 1.23 hours for infants, young children and school children, respectively, and did not differ significantly among the 3 groups. A serum level simulation curve constructed by plotting the mean values for K, ka and Vd did not reveal any substantial deviation from the observed values.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetic and clinical evaluation of aztreonam in neonates and premature infants

In order to study serum concentration and urinary concentration (urinary recovery rate) of aztreonam (AZT), AZT was administered via intravenous bolus injection at dose levels of 10 mg/kg, 20 mg/kg and 50 mg/kg to 7 cases of 4 to 26 days old mature or premature infants nearing cure-stage of various bacterial infections upon the treatment with AZT. Clinical evaluation was made in 19 cases with therapy with AZT alone and 13 cases with combination therapy with AZT + ampicillin (ABPC), with a total of 32 cases. The former group included 10 males and 9 females of 0 to 43 days of age and the latter group included 7 males and 6 females of 6 to 41 days of age. All the cases treated with AZT alone including 5 cases for prophylaxis were evaluable. In the 13 combination therapy cases, however, the effect of AZT was evaluable only in 3 cases excluding the cases in which ABPC-susceptible bacteria were the culprits. 1. Changes in serum concentrations and urinary recovery of AZT. Pharmacokinetics of AZT in serum was examined in 5 matured infants at dose levels of 10 mg/kg in 2 cases and 20 mg/kg in 3 cases. Highest levels were observed with the first sampling at 30 minutes after administration in all the cases with values of 29.1 micrograms/ml with 10 mg/kg dose, and 37.8 micrograms/ml and 55.5 micrograms/ml with 20 mg/kg dose in in cases with ages between 4 and 7 days and 1 case with age above 8 days, respectively. Half-life (T 1/2) values were 3.42, 3.05 and 1.58 hours, respectively for the above three groups of patients. As is described here, the T 1/2 value in the infant with age above 8 days was considerably shorter than the T 1/2 values in infants of younger day-ages. Urinary recovery rates of administered AZT were between 10.4 and 52.6%, showing a large individual diversity. In addition to the above cases, one premature infant was administered with AZT (the dose level: 50 mg/kg) and examined for pharmacokinetic parameters at day-ages of 11 days and 19 days. Serum levels of AZT examined were the highest at 30 minutes after dosage (the first sampling) and were 106.8 micrograms/ml at 11 days of age, and 90.4 micrograms/ml at 19 days of age. Serum levels decreased to 16.2 and 9.6 micrograms/ml, respectively, in 8 hours after dosage, at ages of 11 and 19 days. T 1/2 values were 2.62 and 2.35 hours, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)     

Fundamental and clinical studies of imipenem/cilastatin sodium in the field of obstetrics and gynecology

Fundamental and clinical studies of a new carbapenem antibiotic, imipenem/cilastatin sodium (MK-0787/MK-0791), were carried out to evaluate the drug in treating infections of the female genital organs. The following results were obtained: In 4 patients undergoing hysterectomy, the penetration of MK-0787 and MK-0791 into female genital organ tissues was studied following a 30-minute intravenous drip infusion of MK-0787/MK-0791 500 mg/500 mg. Plasma levels of MK-0787 and MK-0791 in cubital venous blood following the drip infusion peaked at 0 minute with values of 51.2 micrograms/ml and 61.9 micrograms/ml, respectively, then decreased to 1.9 micrograms/ml and 0.7 microgram/ml, respectively, at 201 minutes. MK-0787 penetrated readily to female genital organ tissues and levels of the drug exceeded 0.5 approximately 1.9 micrograms/g in various organ tissues at 201 minutes following an intravenous drip infusion of 500 mg/500 mg of MK-0787/MK-0791. Clinically, MK-0787/MK-0791 was used for the treatment of obstetrical and gynecological infections at a dosage of 500 mg/500 mg twice daily by intravenous drip infusion. Clinical effects of MK-0787/MK-0791 were analyzed in 22 patients, including 9 patients with intrauterine infections, 7 with intrapelvic infections, 5 with adnexitis, and 1 with an external genital infection. Excellent responses were seen in 5 patients (22.7%), good responses in 15 (68.2%), and poor responses in 2 (9.1%). The efficacy ratio was 90.9%. After the treatment, 15 out of 18 isolates were eradicated for an 83.3% eradication rate. All strains of S. epidermidis (2 strains), Eubacterium lentum (1 strain), Peptococcus sp. (1 strain), beta-Streptococcus (1 strain), Gram-positive rods (2 strains), Enterobacter cloacae (1 strain), Bacteroides bivius (1 strain), Pseudomonas sp. (1 strain), Pseudomonas cepacia (1 strain) and Gram-negative rods (1 strain) were eradicated by the MK-0787/MK-0791 treatment. The safety of the drug was analyzed in 22 patients, effects occurred in 3 (13.6%). Among those 3 patients, diarrhea occurred in 1 patient, rash in another and nausea and vomiting in yet another. One patient had an increased BUN after the MK-0787/MK-0791 treatment. In the other 21 patients, no abnormalities in creatinine, GOT, GPT, or T. Bil. values were observed. It may be concluded that MK-0787/MK-0791 is useful for the treatment of obstetrical and gynecological infections.     

Pharmacokinetic and clinical studies on amikacin in neonates

Pharmacokinetic and clinical studies on amikacin (AMK) were performed in neonates and the results obtained are summarized as follows. 1. After intramuscular injection of single doses of AMK at 3 mg/kg, peak serum levels were 6.8 micrograms/ml in a 2-day-old neonate and 7.0 micrograms/ml in a 20-day-old neonate. Serum levels of AMK in the above 2 neonates at 8 hours after injection were 1.5 micrograms/ml and 1.4 micrograms/ml, respectively, and the half-life of AMK was 3.3 hours. After intramuscular injection of single doses of 4 mg/kg of AMK, the mean peak serum level was 8.1 +/- 1.1 micrograms/ml, and half-lives of AMK were 6.1 hours in a 1-day-old neonate and 4.0 hours in a 3-day-old neonate. The mean peak serum level of AMK reached at 1 hour after intramuscular administrations at single dose of 6 mg/kg was 10.5 +/- 0.5 micrograms/ml in a 3-day and a 4-day-old neonates. Serum levels at 8 hours after administrations were 3.1 micrograms/ml and 2.8 micrograms/ml, in the 3-day and the 4-day-old neonates, respectively. Half-lives of AMK in sera were 3.9 hours in the 3-day-old neonate and 3.5 hours in the 4-day-old neonate. 2. In three 2-day-old neonates, the mean peak serum level of AMK after an intravenous drip infusion for 30 minutes at single dose of 3 mg/kg was 10.0 +/- 1.1 micrograms/ml at the end of infusion and serum levels decreased to 2.3 +/- 0.6 micrograms/ml at 6.5 hours after infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Investigation on the use of amikacin in the newborn

The use of amikacin (AMK) in newborns was investigated and the results obtained are summarized as follows. 1. AMK was administered to 3 rabbits at an intramuscular dose of 6 mg/kg. Mean blood levels determined according to methods of bioassay (BIO) and fluorescent immunoassay (FIA) were 28.6 and 22.2 micrograms/ml, respectively, at 30 minutes after dosing. Then, the blood levels declined rapidly. Mean T 1/2 values obtained with the above 2 assay methods were 0.76 and 0.63 hours, respectively. 2. When AMK was administered at a dose of 5.7 mg/kg to a 64 day-old newborn by drip intravenous infusion for 30 minutes, a peak blood level was attained at the end of drip intravenous infusion, which was 20.0 micrograms/ml according to BIO and was 15.5 micrograms/ml according to FIA. The blood levels declined gradually thereafter with a T 1/2 value of 2.33 hours (BIO) or 2.03 hours (FIA). When the drug was administered at 5.3 mg/kg to a 26 day-old newborn using the same infusion method, the peak blood level obtained at the end of drip intravenous infusion was 18.0 micrograms/ml according to BIO and was 14.8 micrograms/ml according to FIA, and T 1/2 values were 4.76 and 3.68 hours, respectively. 3. As there was a close correlation between the values obtained with BIO and with FIA in both rabbits and clinical cases, with a coefficient of 0.990, and also the BIO values could be estimated using a formula of FIA value X 1.2 + 2.2, it would be possible to monitor AMK levels in the blood of patients at bedside using the FIA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Overall clinical evaluation of cefprozil against infections in pediatric fields. Pediatric Study Group for Cefprozil]

Cefprozil (CFPZ, BMY-28100) granule preparation was studied for pharmacokinetic, bacteriological and clinical aspects in the pediatric infections. The results obtained are summarized as follows: 1. Serum concentrations and urinary excretion. The pharmacokinetics of CFPZ in pediatrics was investigated by single oral administration of fine granules at doses of 4.0, 7.5 and 15.0 mg/kg. Peak blood levels of CFPZ were 3.06, 4.62 and 9.65 micrograms/ml, respectively, at 1.00-1.30 hours after each dose and AUCs were 7.44, 12.50 and 27.01 micrograms.hr/ml, respectively. These data showed that Cmax and AUC depended on dose levels. T 1/2 (beta) at these dose levels were 1.03, 0.94 and 1.01 hours, respectively. There were no differences related to dose. Urinary recovery rates in the first 6 hours after administration were 51.5-57.1%. The pharmacokinetics of CFPZ before or after meals were also investigated at a dose of 7.5 mg/kg. Peak blood levels were 4.88 micrograms/ml at 1.17 hours after administration in the fasting state, and 4.30 micrograms/ml at 1.54 hours after administration in the non-fasting state. Delay of Tmax and slight decrease of Cmax were observed in the non-fasting state, but T 1/2 and AUC were 0.91 hour and 12.96 micrograms.hr/ml, respectively, in the non-fasting state, and were similar to those in the fasting state, 0.93 hour and 12.82 micrograms.hr/ml, respectively. Urinary recovery rates in the first 6 hours after administration were 63.8% in the fasting state and 50.7% in the non-fasting state. 2. Clinical results. Clinical efficacies of CFPZ granules in various infectious diseases were studied in 804 cases. Twenty nine cases, mostly viral or mycoplasmal infections, were excluded from the statistical analysis. The clinical efficacy rate in 527 cases with causative bacteria isolated was 97.2%; and in 248 cases from whom no significant isolate had been obtained was 96.0%. The clinical efficacy rate in 475 cases with monobacterial infections (proven by culture of isolates) was 97.3%, and that in 52 case with polybacterial infections was 96.2%. Haemophilus influenzae was isolated mostly from acute respiratory infections. In 88 cases from whom H. influenzae was isolated, clinical efficacy rate was 95.5%. In cases from whom H. influenzae was found concomitant by with Staphylococcus aureus, Streptococcus pyogenes or Streptococcus pneumoniae, the clinical efficacy rates were also high. The bacteriological eradication rate in cases with 582 strains was 83.3%; the eradication rate for Gram-positive organisms was 95.8%; and for Gram-negative organisms, it was 64.2%.(ABSTRACT TRUNCATED AT 400 WORDS)     

Evaluation of the clinical effects of cefotiam against infections in neonates and premature infants

Using cefotiam (CTM) against infections in neonates and premature infants, we obtained the following results: With intravenous administration of the drug to 2 cases each of pyoderma, pneumonia, and fetal infection, the drug was effective in all the cases except in 1 premature infant with pneumonia. Dose levels at individual injections were between 18.6 and 27.8 mg/kg, per dose, with an exception in 1 case of pyoderma (36.4-54.5 mg/kg), and 2 to 4 doses per day were given to each patient. For prophylactic purposes, the drug was administered to 1 case of turbid amniotic fluid and 3 cases of massive aspiration syndrome, and no infection was observed in any case. In a total of 11 cases consisting of the above mentioned 10 cases and an additional case which had been excluded from the evaluation because of the detection of P. aeruginosa, neither side effects nor abnormal laboratory values were recognized. In 5 cases of 4 to 31-day old infants, CTM concentrations in blood were measured after one-time intravenous injection of the drug at a dose level of about 20 mg/kg. Blood concentrations of CTM were low in 1 case with levels of 14.4 and 4.5 micrograms/ml at 30 minutes and 2 hours after the intravenous injection, respectively, whereas they were high in another case with readings of 82 and 65 micrograms/ml. In the remaining 3 cases, however, 30-minute and 2-hour values were between 41 to 52, and 13.5 to 22.8 micrograms/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and therapeutic efficacy of metronidazole at different dosages.

Metronidazole, a drug effective against certain protozoal and anaerobic infections, was given female patients with Trichomoniasis urogenitalis. Group I received twice daily 250 mg of metronidazole (supplied as 250 mg tablets Vagimid). Group II received in a single dose 1.0 g (4 tablets); and group III, 2.0 g (8 tablets). Serum and urine metronidazole levels were measured polarographically. Kinetic parameters were determined from the measured values of the concentration time curve by a computing program. An exact control of the therapeutic result was carried out. In all patients peak serum levels occurred within 1-3 hr and averaged 5.1 +/- 1.7 microgram/ml after 250 mg doses, 19.6 +/- 3.8 microgram/ml after 1.0 g doses and 40.6 +/- 9.3 microgram/ml after 2.0 g doses. About 35% of the administered dose was recovered in the urine in 12 hr and about 50% in 24 hr. Metronidazole shows protein binding of 10-20% equally in vivo and in vitro. Minimum trichomonacidic concentrations of nearly 1 microgram/ml were still present 12 hr after oral application of 250 mg metronidazole, and 24 hr to 36 hr, respectively after 1.0 g and 2.0 g daily doses. The cure rate was 100%. No serious side effects ocurred in any of the patients.     

Pharmacokinetics of cefoperazone after single and multiple doses

The pharmacokinetics of cefoperazone was determined following single and multiple intravenous and intramuscular administrations in man. Ten subjects at each dose level were given eleven successive doses, at 12 h intervals of 500 and 1000 mg i.m. and i.v.. Serum concentrations and urinary excretion were determined in all subjects after the first, fifth and eleventh doses. The first i.m. doses yielded mean peak serum levels of 37 micrograms/ml and 76 micrograms/ml at 1.0 h after injection. The first i.v. doses yielded mean serum levels of 93 and 180 micrograms/ml at 5 min after the injection. No tendency toward drug accumulation was observed on multiple dosage. The pharmacokinetics could be described by a linear, open, two-compartment model of drug distribution. The terminal serum half-life (2.1-2.4 h after i.v. doses and 2.6-2.8 h after i.m. doses) remained essentially constant over the period of the study by dose levels. The no-significant differences of areas under the curve between the two routes, at two doses, show the absolute bioavailability of cefoperazone was about 95% following i.m. administration. The high binding to serum proteins (90%) influences favourably the pharmacokinetic parameters of cefoperazone. It yielded high and prolonged serum concentrations and has very useful distribution properties. These favourable properties, together with its good antibacterial activity, suggest that cefoperazone will be effective in treating bacterial infections in human beings.     

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)     

Experimental and clinical studies on BRL 25000 (clavulanic acid-amoxicillin) granules in the pediatric field

Fundamental and clinical studies have been performed on BRL 25000 (clavulanic acid 1 part-amoxicillin 2 parts) granules in the pediatric field. The antibacterial activities of BRL 25000 and amoxicillin (AMPC) were investigated against clinically isolated and laboratory stocked strains. BRL 25000 was superior to AMPC against strains of E. coli, Salmonella sp. and Klebsiella sp., and similar against Gram-positive cocci. Serum concentrations of AMPC and clavulanic acid (CVA) were measured 0.25, 0.5, 1, 2, 4 and 6 hours after administration of BRL 25000 granules at dose levels of 7.5, 10, 15 and 20 mg/kg. At 7.5 mg/kg peak level of AMPC of 2.69 micrograms/ml was achieved about 2 hours after dosing with a biological half-life of 1.64 hours; corresponding value for CVA was 0.53 micrograms/ml at 1 hour with a T 1/2 of 1.46 hours. At 10 mg/kg, AMPC also peaked after 2 hours (3.82 micrograms/ml) and the T 1/2 was 1.63 hours, whilst for CVA the value was 0.56 micrograms/ml with a T 1/2 of 1.24 hours. Value for AMPC at 15 mg/kg was 5.18 micrograms/ml at 1 hour post dose with a T 1/2 of 1.48 hours, and for CVA 4.01 micrograms/ml at 1 hour with a T 1/2 of 0.89 hour. At the highest dose of 20 mg/kg, AMPC level reached 4.21 micrograms/ml after 2 hours with a T 1/2 of 2.39 hours, and the CVA peak was 1.64 micrograms/ml at 1 hour with a T 1/2 of 1.01 hours. The 6 hours urinary recovery of AMPC and CVA following administration of the BRL 25000 granules ranged from 38-64% and 2-33%, respectively. In the clinical studies, the BRL 25000 granules are administered to 15 cases with pediatric infections and the clinical response was excellent or good in all cases treated (100%). Bacteriological investigation was performed on 13 strains from 12 cases and all strains were eradicated (100%). Regarding side effects, elevation of eosinophil was observed in 1 case and vomiting in 3 cases.