Laboratory and clinical studies of norfloxacin in pediatric field

We have carried out laboratory and clinical studies on norfloxacin (NFLX, AM-715). The results are summarized as follows. NFLX was given through oral administration to one child each at dose levels of 1.7 mg/kg, 2.4 mg/kg and 3.2 mg/kg. After administration, peak serum levels of NFLX obtained for the 3 dose levels were 0.16 micrograms/ml at 1 hour, 0.69 micrograms/ml at 2 hours, 0.81 micrograms/ml at 1 hour, respectively, and half-lives were 2.5 hours, 1.8 hours and 2.7 hours, respectively. NFLX was given through oral administration to 2 children at a dose level of 4.4 mg/kg and to another child at a dose level of 4.8 mg/kg. After administration, mean peak serum levels of NFLX obtained were 1.17 +/- 0.48 micrograms/ml and half-lives were 3.0 +/- 0.5 hours. Urinary excretion rates of NFLX were 14.5% and 28.4% in the first 8 hours after administration of 1.7 mg/kg and 3.2 mg/kg, respectively, and 29.1% in the first 6 hours after administration of 2.4 mg/kg. Mean urinary excretion rates of NFLX were 38.5 +/- 13.0% in the first 8 hours after administration of 4.4 mg/kg and 4.8 mg/kg. Treatment with NFLX was made in 33 cases of pediatric bacterial infections including 5 cases of tonsillitis, 14 cases of enteritis, 10 cases of UTI and 1 case each of bronchitis, balanoposthitis, impetigo and pustulosis. Results obtained were excellent in 14 cases, good in 15 cases. No significant side effect due to the drug was observed in any cases.     

Pharmacokinetics and clinical studies of norfloxacin in the pediatric field

Norfloxacin (NFLX) tablets with a potency of 50 mg/tablet or 100 mg/tablet were administered at doses of 1 to 4 tablets (1.5 to 6.1 mg/kg) orally 30 minutes before meals to 12 children with ages ranging from 8 years 9 months to 12 years 5 months, and serum/urinary NFLX levels and urinary recovery rates were determined. The drug sensitivity tests for NFLX and 10 other drugs were conducted against 128 strains of Shigella sonnei (10(6) CFU/ml) which had been isolated from pediatric patients with bacillary dysentery. In order to evaluate clinical and bacteriological effects of NFLX and its safety in the pediatric field, NFLX 50 mg tablets were administered t.i.d. (mean 8.3 mg/kg) for 5 days to 42 pediatric patients with bacillary dysentery. Similarly, this drug was administered in b.i.d. or t.i.d. (mean 6.7 mg/kg) for 4 days to 4 pediatric patients with urinary tract infections. The following results were obtained: 1. According to the dosage, the subjects were divided into 3 groups with dose levels 1.5-2.8 mg/kg, 3.1-4.7 mg/kg and 5.2-6.1 mg/kg. These groups had 5, 2 and 5 subjects, respectively. Mean serum drug concentrations for the 3 dosage groups were at peak levels of 0.27, 0.64 and 1.51 micrograms/ml at 4, 2 and 1 hour(s) after administration, respectively. Pharmacokinetic parameters for these dosage groups were as follows: Tmax values were 3.0, 3.0 and 1.2 hours; Cmax values were 0.32, 0.78 and 1.56 micrograms/ml; serum half-lives were 2.2, 2.4 and 2.3 hours; and AUCs were 1.65, 3.98 and 6.06 micrograms.hr/ml, respectively. Thus, dose-dependent responses were observed among the 3 dosage groups. 2. Mean peak urinary drug concentrations for the 3 dosage groups were 45.8, 109.2 and 215.1 micrograms/ml, respectively, and the peaks appeared 2-4 hours after administration. Mean recovery rates up to 8 hours after administration were 18.3%, 24.5% and 28.7%, respectively for the 3 dosages. 3. In a drug sensitivity test against 128 strains of S. sonnei, the most frequent MIC value of NFLX was 0.78 micrograms/ml against 65 strains, followed by 0.39 micrograms/ml for 56 strains. Together, these strains accounted for 94.5% of the strains tested. No resistant strain to this drug was observed and the antibacterial activity of this drug was second only to colistin, similar to that of ofloxacin, better than those of enoxacin and seven other drugs. 4. Clinical efficacy rate of NFLX against bacillary dysentery was 95.2% in 21 cases in which the evaluation was possible.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetics of cefixime in patients with impaired renal function

Cefixime (CFIX) was given orally in a single dose of 100 mg to 7 patients with varying degrees of impaired renal function (Ccr 12.0-56.7 ml/min) and serum concentrations and urinary excretion rates were measured with time for the first 24 hours by the bioassay method to investigate in vivo pharmacokinetics of the drug. The results obtained are summarized as follows. The mean peak serum concentration of CFIX in 3 patients with moderately impaired renal function (group I: Ccr greater than or equal to 30-less than 60 ml/min) was 2.04 micrograms/ml at 6 hours after dosing and gradually declined to 0.10 microgram/ml at 24 hours after dosing. The half-life was 4.15 hours. The mean peak serum concentration of CFIX achieved was 2.27 micrograms/ml at 8 hours after dosing in 4 patients with severely impaired renal function (group II: Ccr greater than or equal to 10-less than 30 ml/min) and the concentration of CFIX was 0.99 microgram/ml even after 24 hours. The half-life was prolonged to 11.05 hours. There was no great difference between groups I and II in the first 24-hour urinary excretion rates. However, the first 4-hour urinary excretion accounted for 2.14% of the administered dose of CFIX in group I but only 0.47% in group II. Urinary concentrations of CFIX peaked at 4-6 hours after dosing in both groups, and thereafter gradually decreased in group I. Whereas, they did not decline much in group II until 24 hours after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical efficacy and pharmacokinetic evaluation of ceftizoxime in neonates and young infants

Thirteen neonates and young infants, including 5 infants with very low birth weight, were treated with ceftizoxime (CZX) and its clinical efficacy and side effects were evaluated. The ages of the patients ranged from 0 to 96 days, and their body weights ranged from 580 to 5,050 g. Doses given were 20-54 mg/kg every 6 to 12 hours for 2.5 to 7.5 days. Two infants with sepsis, one with urinary tract infection, one with sepsis and urinary tract infection, and 1 with fetal infection were considered to have responded satisfactorily to the CZX treatment. The drug was well tolerated and side effects was not apparent. Pharmacokinetic studies were done on CZX in 8 patients including 4 infants with very low birth weight. Their ages ranged from 2 to 91 days, and body weights from 545 to 5,050 g. Serum concentrations at 2 hours after single 20 mg/kg intravenous bolus injections were 19.2 to 44.2 micrograms/ml and the levels were 2.11 to 26.3 micrograms/ml at 8 hours. Elimination half-lives of CZX ranged 1.90 to 9.57 hours in these patients. In 2 infants with very low birth weights with ages 7 and 91 days, half-lives were as long as 9.57 and 8.24 hours, respectively. Urinary recovery in 6 hours was 31.9-66.9% in 5 patients. Urine concentrations of the drug in 24 samples collected at various time from the 7 patients ranged from 130 to 3,219 micrograms/ml. Influence of CZX on the fecal flora was studied in 1 patient given 20 mg/kg X 4/day of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phase I study of cefixime, a new oral cephalosporin

The tolerance to and pharmacokinetics of cefixime, a new oral cephalosporin, were evaluated in healthy volunteers given the drug in single doses of 50, 100 and 200 mg and repeated doses of 200 mg bid for 14 days. In the repeated-dose study, there were mild and transient subjective symptoms such as soft stools, diarrhea, and anorexia, which disappeared without additional treatment during the dosing period. Slight increases in eosinophil and serum amylase levels were also observed. The serum concentrations of cefixime peaked at 0.71, 1.17, and 2.08 micrograms/mL on average, four to five hours after dosing with 50, 100, and 200 mg, respectively, and the half-lives were 2.54, 2.38, and 2.29 hours. Serum concentrations and urinary recoveries after dosing with 100 mg were little affected by food ingestion. There was no evidence of cefixime accumulation in the body by repeated dosing since mean serum concentrations and urinary recoveries were almost the same on the first, third, seventh, and 14th days of dosing.     

Laboratory and clinical studies on norfloxacin in the pediatric field

In bacteriological, pharmacokinetic and clinical studies on norfloxacin (NFLX, AM-715), the following results were obtained: 1. Antibacterial activity of NFLX, nalidixic acid (NA), amoxicillin (AMPC), cefaclor (CCL), erythromycin (EM) and fosfomycin (FOM) against clinically isolated bacteria was examined, and it was found that MIC80 of NFLX against Staphylococcus aureus was 3.13 micrograms/ml, thus NFLX exhibited stronger antimicrobial activity than NA, AMPC, CCL, EM and FOM. NFLX also showed good activities to those strains of S. aureus which were resistance to NA, AMPC, CCL, EM and FOM. 2. MIC80 of NFLX against Escherichia coli was 0.05 micrograms/ml or lower, thus NFLX showed better activity than NA, AMPC, CCL, EM and FOM. 3. In single oral administration at fasting of NFLX at dose levels of 1.5-2.4 and 2.5-3.4 mg/kg in tablet form mean peak values of serum concentration were 0.32 micrograms/ml reached in 1 hour and 0.38 micrograms/ml in 2 hours, T1/2's obtained were 1.7-4.0 and 2.2-2.9 hours and AUC's were 1.54 +/- 0.52 and 2.02 +/- 0.93 micrograms.hr/ml, respectively. Urinary recovery rates of 11.6-46.9%, 13.8-35.4% in 6-8 hours were demonstrated with the 2 ranges of dose levels, respectively. 4. NFLX was administrated to 34 patients consisting of 8 cases of acute pneumonia, 3 cases of acute tonsillitis, 3 cases of bacterial colitis, 19 cases of urinary tract infections and 1 case of purulent parotitis. The clinical efficacy rate was 97.1% including 34 cases with excellent results in 28, good in 5 and fair in 1. 5. The bacterial eradication rate was 96.8% (30/31) with one exception of a Campylobacter jejuni strain. 6. NFLX was given to patients according to a dosing regimen with 4.5-21.4 mg/kg/day dose levels for 3 doses daily except 1 case of UTI where 2 daily doses were given daily. 7. No adverse reactions were observed. Abnormal laboratory test value was obtained in 1 case where eosinophilia was found. The above results have suggested that NFLX is a useful and safe antimicrobial agent against bacterial infections in children.     

Effect of norfloxacin on bacterial flora in human feces

Norfloxacin (NFLX), a synthetic oral antibacterial agent of quinolone carboxylic acid, was given orally for 5 full days at a dose of 200 mg, three times daily after each meal to healthy normal men with ages between 22 and 25 years weighing 53.0 to 84.0 kg (average 67.0 kg). The actual regimen followed was that the drug was administered twice after lunch and supper on the first day of dosing, and once after breakfast on the last day of dosing. On the 5th day before the start of dosing, on the first, 3rd and 5th days (last dosing day) of dosing, and on the 3rd, 5th, 10th and 20th days after the end of dosing, effects of the drug on the fecal flora were examined and its fecal levels were determined. Susceptibilities against NFLX and nalidixic acid (NA) of various fecal isolates from 7 men were determined. Adverse effects and influences on clinical laboratory tests were also examined. The results obtained are summarized below. 1. Following the drug administration, a transient decrease or disappearance of Escherichia coli, Klebsiella sp., Citrobacter sp. and Enterobacter sp. of Enterobacteriaceae was noted. The 3 strains other than E. coli were isolated from increasing number of cases after the end of dosing. No constant trend was observed in the isolation of Proteus sp. Organisms belong to Enterobacteriaceae were isolated only in 4 and 2 cases after 3 and 5 days of the start of dosing, respectively, but then gradually increased to the predose level. Among other Gram-negative bacteria, no constant trend was noted in the isolation frequency of Plesiomonas sp. Pseudomonas sp. was isolated from 6 and 5 cases on the 3rd day after dosing and on the 3rd day after the end of dosing, respectively; the frequency of isolation increased after dosing. Gram-positive bacteria such as Staphylococcus sp. were isolated with a reduced frequency on the 3rd day of dosing. However, the number of isolates increased in all cases both on the 5th day of dosing and on the 3rd day after the end of dosing, and then decreased. No change was noticed in the number of isolates of Enterococcus sp., and no constant trend was observed for Micrococcus sp. and YLO. The average count of the whole aerobic bacteria did not change. Some strains decreased significantly after the start of dosing. 2. Among anaerobes, Bacteroides fragilis and other Bacteroides were isolated on every test day.(ABSTRACT TRUNCATED AT 400 WORDS)     

Basic and clinical studies on norfloxacin in the pediatric field

Pharmacokinetic , bacteriological and clinical studies on norfloxacin (NFLX), a quinolone-carboxylic acid antibacterial agent, were conducted in the pediatric field. 1. Serum concentrations and urinary excretion of NFLX after single dose of 2.2 approximately 5.6 mg/kg (mean 4.4 +/- 1.2 mg/kg) were determined in 13 children with ages between 6 and 11 years. The mean peak serum concentration of the drug was 0.37 +/- 0.20 micrograms/ml at 2 hours after administration. The mean half-life of the drug in serum was 2.8 +/- 0.4 hours and the serum concentration at 8 hours was 0.11 +/- 0.06 micrograms/ml. The mean urinary concentration reached a maximum of 125.2 +2- 166.2 micrograms/ml in pooled urine from 0 to 2 hours and the mean urinary recovery rate in the first 8 hours after administration was 22.1 +/- 6.0%. A dose-response relationship was observed between doses/body weight and peak serum concentrations. 2. The clinical efficacy, bacteriological efficacy and the safety of NFLX were evaluated in 65 pediatric patients with ages between 2 years 10 months and 15 years 7 months with infections. In 62 assessable cases (acute purulent tonsillitis 9 cases, acute pneumonia 3 cases, chronic rhinitis 1 case, urinary tract infections 15 cases, and acute colitis 34 cases), clinical efficacies were excellent in 48 cases, good in 13 cases, and fair in 1 case with an overall efficacy rate of 98.4%. Staphylococcus aureus 1 strain, Staphylococcus epidermidis 1 strain, Escherichia coli 10 strains, Salmonella sp. 5 strains, Morganella morganii 1 strain, Pseudomonas aeruginosa 3 strains, Haemophilus parainfluenzae 1 strain and Campylobacter jejuni 12 strains were isolated from the patients as pathogens. Bacteriologically, all of these strains were eradicated except that 3 strains of C. jejuni only decreased. With regard to side effects, dizziness and nausea were observed in 1 case each but they were slight and the continuation of the treatment was possible. No abnormal laboratory test data were observed. From the above results, NFLX was considered to be a useful drug for the treatment of pediatric infections.     

Pharmacokinetic, bacteriological and clinical studies on aztreonam in neonates

Pharmacokinetic, bacteriological and clinical studies on aztreonam (AZT) were performed in neonates. The results obtained are summarized as follows. 1. Plasma levels and urinary excretion of AZT were determined in 18 neonates with ages between 1 and 30 days (gestation periods were 36 to 40 weeks and birth weights were 1,890 to 4,300 g) and in 2 infants with 54 and 60 days of age (gestation periods were 36 and 40 weeks, and birth weights were 2,300 and 3,300 g, respectively) upon one-shot intravenous injection of AZT 10 mg/kg (7 cases) or 20 mg/kg (11 cases) to the 18 neonates and 20 mg/kg to the 2 infants. Ampicillin (ABPC) 25 mg/kg was simultaneously injected to 5 cases of the neonates given AZT 20 mg/kg by one-shot intravenous injection and plasma concentrations of ABPC in these 5 cases were also studied. Plasma concentrations in neonates at 0.5 hour after intravenous injection of AZT 10 mg/kg were 11.5 to 27.6 micrograms/ml (average 20.3 +/- 5.5 micrograms/ml) and decreased with half-lives of 2.72 to 5.70 hours (average 3.81 +/- 1.28 hours), and the plasma levels at 8 hours after administration were 3.3 to 8.7 micrograms/ml (average 5.8 +/- 2.5 micrograms/ml). In the cases given AZT at 20 mg/kg, plasma levels at 0.5 hour were 12.4 to 48.8 micrograms/ml (average 35.9 +/- 11.6 micrograms/ml) and decreased with half-lives of 1.69 to 4.14 hours (average 2.94 +/- 0.76 hours) and AZT levels at 8 hours were 1.1 to 10.6 micrograms/ml (average 5.6 +/- 3.6 micrograms/ml). Urinary recovery rates in the first 8 hours after intravenous injection of the 10 mg/kg group were 15.5 to 61.9% (average 37.8 +/- 21.8%) and 16.3 to 62.2% (average 43.5 +/- 16.2%) for the 20 mg/kg group. Plasma concentrations in infants after administration of AZT 20 mg/kg were 33.0 to 35.6 micrograms/ml (average 34.3 +/- 1.8 micrograms/ml) at 0.5 hour and decreased with half-lives of 1.76 to 3.77 hours (average 2.77 +/- 1.42 hours) and AZT plasma levels at 8 hours were 1.4 to 5.8 micrograms/ml (average 3.6 +/- 3.1 micrograms/ml). Urinary recovery rates were 35.4 to 64.8% (average 50.1 +/- 20.8%). These results suggested that AZT shows a dose-dependent, high plasma concentration even in the neonatal period, as well as good urinary excretion from an early stage of the administration.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetics of BMY-28100 in multiple administration

A multiple dose trial of BMY-28100, a new oral cephalosporin, was performed in volunteers, in order to evaluate its safety and pharmacokinetics. BMY-28100 was administered orally 250 mg t.i.d. for 7 days to seven healthy adult males. No side effects nor abnormal laboratory findings were observed. Peak levels of serum concentration and half-lives after the first and 19th administrations were 4.45 and 4.83 micrograms/ml and 1.3 and 1.1 hours, respectively. Urinary recoveries in 24 hours were 53.4% on day 1 and 56.2% on day 7. There was no tendency towards accumulation in blood upon continuous daily dosing of 250 mg t.i.d.     

Fundamental and clinical studies on cefamandole in pediatric treatment (author's transl)]

Cefamandole (sodium salt) was administered to total 32 cases of bacterial infectious diseases of children, and in 3 cases, there were investigated of these absorption and excretion. The results are as follows; 1. Blood levels: Cefamandole was given intravenous dose of 25 mg/kg to 3 children. The blood level of 15 minutes after intravenous injection was 140.4 micrograms/ml in average, and 0.3 micrograms/ml in average at 4 hours after intravenous injection. T 1/2 was 13.9 minutes. 2. Urinary concentration: Within 6 hours after intravenous injection, 51.8% of the drug was recovered in average from the urine and the urinary concentration reached to 3,050 micrograms/ml in average (0 approximately 2 hours), 1,262 micrograms/ml in average (2 approximately 4 hours), 41 micrograms/ml in average (4 approximately 6 hours) after injection. 3. Clinical results: The drug was given 109 mg/kg/day (t.i.d. or q.i.d.) by intravenous route. The duration of administration was 11 days in average. The overall efficacy rate was 97%. In bacteriological results, excellent in 2, failure in 1, out of 3 strains. As side effects vascular pain was observed in 3 cases at the intravenous injection, and eosinophilia in 2 cases.     

Pharmacokinetic and clinical studies of cefmenoxime in neonates and premature infants

Serum concentrations and urinary recovery rates of cefmenoxime (CMX) were determined in 41 mature and premature infants (with ages 0-24 days) after one shot intravenous injection of 10, 20 (1-hour intravenous drip infusion was also carried out) or 30 mg/kg for treatment and prophylaxis of various infections. Because the number of cases included was small, a comparison study was conducted by classifying them into 3 groups; 3 days or younger, 4 to 7 days, and 8 days or older, rather than dividing them into groups of mature and premature infants. Clinical evaluation was conducted in 7 male and 1 female cases 1 to 29 days old, whose diseases comprised 1 case each with septicemia, purulent otitis media and phlegmonous cellulitis, 3 with pneumonia and 2 with urinary tract infection. 1. Changes in serum concentrations and urinary recovery rates (1) Intravenous bolus injection of 10 mg/kg: Serum concentrations of the drug in the 3 age groups peaked at 28.9, 29.5 and 29.1 micrograms/ml, respectively, all at 30 minutes after the drug administration, and thereafter gradually declined. The mean level in the 3rd group was the lowest at 1.9 micrograms/ml at 6 hours. Average serum half-lives of CMX were shorter in older subjects, 3.0, 1.9 and 1.4 hours, respectively in the 3 groups. Urinary recovery rates were relatively high, 68.9 to 84.9% in the 3 cases examined during the first 6 hours, and 15.4 to 66.2% during the first 2 hours. (2) Intravenous bolus injection of 20 mg/kg: Serum concentrations of the drug in the 3 groups peaked at 65.2, 60.5 and 65.8 micrograms/ml, respectively, all at 30 minutes after the drug administration, with no significant differences noted among the groups. The levels gradually declined thereafter in all groups, but remained rather high at 20.1, 6.5 and 9.5 micrograms/ml, respectively, at 6 hours. Average serum half-lives of CMX were 3.5, 1.7 and 1.9 hours, respectively. The inversion of values obtained between the 2nd and 3rd groups appears to be attributable to that all of the 3rd group were premature infants, and the body weight of 2 cases of them were less than 2,000 g each. Urinary recovery rates ranged widely from 37.0 to 89.4% in the 4 cases examined during the first 6 hours. (3) One-hour intravenous drip infusion of 20 mg/kg: Serum concentrations of the drug in the 3 groups peaked at 57.7, 60.2 and 72.4 micrograms/ml, respectively, all at the termination of the drug infusion.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetics and clinical studies of ceftizoxime in newborn and premature infants

Serum concentrations and urinary recovery rates of ceftizoxime (CZX) were investigated in 13 mature newborns and 16 premature newborns (with ages 1-17 days) after one shot intravenous injection of 10 and 20 mg/kg, respectively, for treatment and prophylaxis of various infections. Obtained data were studied comparatively among the 3 groups, i.e. the 1st group (age: 0-3 days), 2nd group (age: 4-7 days) and 3rd group (age: 8 days or older). The clinical investigation was made in 9 male and 6 female newborns aged 3-34 days including 4 pediatrics patients with septicemia (1 with purulent meningitis, 1 with urinary tract infection, 1 with Staphylococcal pneumonia and 1 without complication), 1 with maxillary sinusitis, 5 with bronchopneumonia and 5 with urinary tract infections. 1. Serum concentrations and urinary recovery rates (1) Mature newborns given one shot intravenous injection of 10 mg/kg Serum concentrations of the drug in the 1st, 2nd and 3rd groups in 30 minutes after one shot intravenous injection of 10 mg/kg peaked at 18.9-23.3 micrograms/ml, without any significant differences, and thereafter gradually declined to 2.10-4.99 micrograms/ml at 8 hours. Serum half-lives were shorter in older subjects and values in the 3 groups were 3.89, 2.99 and 2.35 hours, respectively. Urinary recovery rates ranged from 55.5% to 70.0% at 8-6 hours in the 3 patients. (2) Mature newborns given one shot intravenous injection of 20 mg/kg Serum concentrations of the drug in the 3 groups peaked in 30 minutes after one shot intravenous injection of 20 mg/kg at, respectively, 36.9, 41.4 and 38.4 micrograms/ml, and thereafter they gradually declined to 9.0, 7.3 and 4.5 micrograms/ml at 8 hours, respectively. Serum half-lives were shorter in older subjects and values in the 3 groups were 3.59, 2.93 and 2.49 hours, respectively. Urinary recovery rates ranged from 43.5 to 78.2% within 12 hours in 2 patients, within 8 hours in 2 patients and within 6 hours in 1 patient. (3) Premature newborns given one shot intravenous injection of 10 mg/kg Serum concentrations of the drug in the 3 groups peaked in 30 minutes after one shot intravenous injection of 10 mg/kg at, respectively, 27.9, 21.5 and 23.0 micrograms/ml, and they gradually declined thereafter to 10.8, 6.2 and 6.5 micrograms/ml at 8 hours, respectively. Serum half-lives were shorter in older subjects and values in the 3 groups were 5.28, 4.43 and 4.24 hours, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)     

Laboratory and clinical studies on norfloxacin in pediatrics

Norfloxacin (NFLX, AM-715) is a new quinolone antibacterial agent. In the present study, we carried out laboratory and clinical investigations on NFLX in the field of pediatrics. The obtained results are summarized as follows. 1. NFLX was very active against Escherichia coli, Salmonella sp., Klebsiella sp., Enterobacter sp. and Pseudomonas aeruginosa among Gram-negative rods. Antibacterial activities of NFLX against Gram-positive cocci were lower than those against Gram-negative rods but superior to activities of usual quinolone agents. MIC values of NFLX against Campylobacter jejuni were distributed in a range of less than or equal to 0.05-0.78 micrograms/ml. 2. A peak serum level of 0.49 micrograms/ml was observed in 2 subjects and its urinary recoveries were 13.7%, 21.5%, respectively. 3. Clinical efficacies to NFLX were excellent in 25 patients and good in 9 patients with a efficacy rate of 92%. In a bacteriological examination, causative organisms were eradicated with an eradication rate of 87%. 4. No side effects were observed except eosinophilia in 1 patient. These findings indicate that NFLX will be useful and safe drug against bacterial infections in pediatrics.     

Pharmacokinetic, bacteriological and clinical studies in the pediatric field on norfloxacin

We have evaluated norfloxacin (NFLX), a fluoroquinolone agent, in tablet form for its efficacy and safety in the field of pediatrics. 1. Mean serum concentrations of NFLX following oral administration to 3 children at dose levels of 3.2 mg/kg, 3.7 mg/kg and 5.4 mg/kg were, respectively, 0.7 microgram/ml, 0.18 microgram/ml and 0.64 microgram/ml at 2-4 hours. Mean serum half-lives (T1/2) of NFLX were 2.5-2.9 hours and mean urinary recovery rates in the first 6 hours after administrations were 7.1-30.7%, depending on dose levels. 2. Antibacterial activities of NFLX against clinically isolated 30 organisms from children were determined. MIC of NFLX against Staphylococcus aureus was similar to that of ABPC, 0.39-25 micrograms/ml. MIC of NFLX against Escherichia coli was approximately less than or equal to 0.10 microgram/ml. This MIC value was lower than other antibiotics. MIC of NFLX against Vibrio parahaemolyticus was less than or equal to 0.10 microgram/ml. 3. NFLX was administered to 30 patients (7 patients with Salmonella enteritis, 7 patients with Campylobacter enteritis, 5 patients with other enteritis, 1 patient with bacillary dysentery, 8 patients with urinary tract infection, 2 patients with skin soft tissue infection). The clinical responses of these 30 patients were as follows; excellent: 24 patients, good: 4 patients. The efficacy rate was 93.3%. 4. The bacteriological efficacy rate of NFLX against clinically isolated 29 organisms from children was 75.9%, including 3 cases in which other antimicrobial agents had been ineffective. Especially against Salmonella spp. was superior to other agents tested. 5. Neither clinical adverse reaction nor abnormal laboratory data was found in any of these 33 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic and clinical studies on cefmenoxime in newborn infants

Pharmacokinetic and clinical studies on cefmenoxime (CMX) were performed in infants given by the drug intravenous drip infusion or one shot intravenous injection. The results obtained are summarized as follows. 1. Serum concentrations of CMX in infants given CMX at 10 mg/kg by intravenous drip infusion peaked at 12.0 to 26.5 micrograms/ml at the termination of the administration, and the levels were 8.62 to 26.3 micrograms/ml in 1 hour after dosing. Half-lives were 2.9 to 3.8 hours. 2. Serum concentrations of CMX in infants given the drug at 20 mg/kg by the same manner for 30 minutes to 1 hour peaked at 40.8 to 74.3 micrograms/ml at the termination of the administration, and drug levels decreased to 17.6 to 45.4 micrograms/ml in 1 hour after dosing. Half-lives were 0.8 to 2.7 hours. Those of CMX in infants given the same dose by one shot intravenous injection peaked at 61.7 to 90.6 micrograms/ml immediately after dosing, and decreased to 22.3 to 48.2 micrograms/ml at 1 hour. Half-lives were 1.2 to 2.7 hours. 3. As described above, dose-response was observed between the doses of 10 mg/kg and 20 mg/kg. 4. Urinary recovery rates were 2.6 to 47.7% during the first 6-8 hours in most of 1 to 2 day-old infants, and 17.6 to 72.4% in most of 5 day-old or older ones. 5. Twelve infants with various bacterial infections were given CMX by intravenous injection or drip infusion. Clinical efficacies of CMX were excellent or good in all the 9 infants with pneumonia, septicemia, amniotic fluid-aspiration syndrome or intra-placental infection etc., while 3 cases were excluded: 1 each with congenital syphilis (0 day old), acute bronchitis (56 days old) and whooping cough (54 days old). 6. Dosages of CMX used in the present study were 33 to 79 mg/kg/day, and durations of treatment ranged from 4 to 13 days. No abnormal laboratory test values were observed. Moreover, neither systemic nor local adverse effects attributable to CMX were encountered in any of the infants.     

Clinical studies on cefprozil granules in pediatrics]

Cefprozil (CFPZ, BMY-28100) granules was administered to a group of pediatric patients. The new oral cephalosporin, CFPZ, was evaluated clinically in 42 pediatric patients, and a pharmacokinetic study was performed in 6 patients. Serum and urinary concentrations of CFPZ were determined in 6 patients who were given single dose of 7.5 or 15.0 mg/kg. Serum concentrations were determined at 1, 2, 3, 4 and 6 hours after dosing. Urinary concentrations were measured for periods of 0-6 hours after dosing. With oral administrations of 7.5 mg/kg and 15.0 mg/kg, peak serum concentrations were 2.13 micrograms/ml and 6.22 micrograms/ml, respectively, at 2 hours, and biological half-lives were 1.06 hours and 1.36 hours, respectively. Urinary recovery rates were 44.8% and 56.1%. The clinical evaluation was conducted in 41 patients including 16 patients with acute tonsillitis, 8 patients with lacunar tonsillitis, 4 patients with scarlet fever, 3 patients with acute bronchitis, 1 patient each with pertussis, furuncle, impetigo and lymphadenitis, and 6 patients with urinary tract infections. The ages of the patients were 10 month to 11 years 1 month, and they were treated with CFPZ at doses ranging 9.0-45.0 mg/kg daily for 3-14 days, the overall clinical efficacy rate was 92.7%. An eradication rate of 79.2% was achieved for 28 strains of 8 species identified in the patients. No side effects were observed. Abnormal laboratory test results obtained were eosinophilia in 2 patients.     

Disposition of amiodarone in rats after single and multiple intra-peritoneal doses.

The pharmacokinetics of amiodarone was studied after single and multiple dosing in two groups of male Wistar and Albino rats. The first group (40 rats) received a single intraperitoneal (i.p.) dose of amiodarone (100 mg/kg) and 4 rats sacrificed 1, 2, 4, 6, 12, 18, 24, 36, 48 and 72 hours post dosing. The second group (42 rats) received amiodarone (50 mg/kg, i.p., daily) for 5 days a week for 5 weeks and 6 rats were sacrificed at 1, 2, 3, 4, 5, 6 and 8 weeks. Rats of both group were sampled for blood, heart, lung and fat and the concentrations of amiodarone in these samples were determined using. The elimination of amiodarone from plasma after single dose followed a biphasic pattern with a terminal half-life of 54.7 +/- 8.2 hours. The concentrations of amiodarone in the tissues were halved within 26.8, 34.9 and 37.45 hours in the heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat after single dose were 1.24 micrograms/ml, 1.73 micrograms/mg, 7.61 micrograms/mg and 29.01 micrograms/mg, respectively. The concentration of amiodarone after multiple dosing were halved within 8.4, 5.5, 6.4 and 9.8 days, for the plasma, heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat during multiple doses were 0.97 microgram/mg, 7.63 micrograms/mg and 65.01 micrograms/mg respectively. In conclusion, after multiple dosing, the elimination half-life of amiodarone and its fat contents were 3.7 and 2.8 times greater than that after single dosing. The excessive amount of amiodarone observed in fat tissues after multiple dosing is probably the reason for the prolonged elimination half-life. Based on the elimination half-lives data, the time to steady state is about two weeks and the drug should be withheld for less than a mont if a patient required discontinuation because of serious adverse effects.     

Basic studies of cefotiam (author's transl)

The basic studies of cefotiam (CTM) were performed, and the following results were obtained. 1. One shot intravenous injection of 40 mg/kg of CTM (1) Serum levels: The mean levels of CTM in 3 children were 133.9 micrograms/ml after 15 minutes, 71.5 micrograms/ml after 30 minutes 32.6 micrograms/ml after 1 hour, 9.2 micrograms/ml after 2 hours, 2.5 micrograms/ml after 4 hours, 0.9 microgram/ml after 6 hours. The serum half life of CTM was approximately 1.2 hours on beta-phase. (2) Urinary excretion: The mean urinary excretions were 39.4% over 3 hours, 44.7% over 4 hours, 45.7% over 6 hours. 2. 1 hour-drip infusion of 40 mg/kg of CTM (1) Serum levels: The mean serum levels of CTM in 4 children were 140.1 micrograms/ml at immediately after drip infusion was completed, 10.6 micrograms/ml after 1 hour, 3.8 micrograms/ml after 2 hours, 1.4 micrograms/ml after 3 hours, 0.5 microgram/ml after 5 hours. The serum half life of CTM was approximately 1.0 hour on beta-phase. (2) Urinary excretions: The mean urinary excretions were 42.9% over 2 hours, 48.0% over 4 hours, 48.7% over 6 hours. 3. Bioactive metabolite in serum and urine: No bioactive metabolites were observed in either serum or urine after administration of 40 mg/kg of CTM.     

Disposition of Tablet and Capsule Formulations of Digoxin in the Elderly

Study Objective . To compare digoxin tablets and liquid-filled capsules with respect to excretion of the drug and its metabolites in urine and feces at steady state. Design . A randomized, crossover trial, each period lasting 3 weeks, with no washout period. Setting . A university hospital. Patients . Six patients, five of whom were elderly, with histories of gastrointestinal disorders, such as hypochlorhydria, intestinal bacterial overgrowth, and inflammatory bowel disease. Interventions . The patients received digoxin once/day in either tablet or capsule form for 3 weeks, and then were switched to the other formulation. Total urinary and fecal excretion from the last 3 days of each regimen were analyzed for the drug and metabolites. Measurements and Main Results . No statistically significant differences were found between tablets and capsules in recovery of digoxin or its metabolites in urine or feces (p=0.05). One subject had a 4-fold increase in urinary drug excretion and 50% decrease in fecal excretion after taking the capsules compared with tablets. Intersubject variability in extent and type of metabolite excretion was greater than intrasubject variability. Conclusions . Fecal analyses may be an accurate way to classify patients as formers of digoxin reduction products.