Pharmacokinetic studies on oral antibiotics in pediatrics. II. A pharmacokinetic study on cefteram pivoxil in pediatrics

A pharmacokinetic study on cefteram pivoxil (CFTM-PI) granules and tablets for pediatric use was performed, and pharmacokinetic parameters were calculated using the one-compartment open model with a time lag. 1. Twelve school children were administered orally with CFTM-PI granules at a dose level of 3 mg/kg either at 30 minutes before meal or 30 minutes after meal on a crossover design, and serum concentrations and urinary excretion rates of CFTM were determined. Tmax, Cmax, T 1/2 and urinary excretion rate following the administration before meal were 1.3 +/- 0.1 hours, 1.35 +/- 0.11 micrograms/ml, 1.21 +/- 0.07 hours and 13.4 +/- 1.5%, respectively. Tmax, Cmax, T 1/2 and urinary excretion rate following the administration after meal were 2.9 +/- 0.3 hours, 1.08 +/- 0.09 microgram/ml, 1.72 +/- 0.26 hours and 23.3 +/- 2.2%, respectively. Earlier Tmax, higher Cmax and lower urinary excretion rate were observed when the drug was administered before meal than when administered after meal. 2. Six school children were administered orally with CFTM-PI granules at 30 minutes after meal at a dose level of either 3 mg/kg or 6 mg/kg on a crossover design, and serum concentrations and urinary excretion rates of CFTM were determined. Cmax at a dose level of 3 mg/kg was 1.50 +/- 0.26 microgram/ml, Cmax at a dose level of 6 mg/kg was 2.58 +/- 0.29 micrograms/ml. There existed dose response. 3. Eighteen school children, 10 younger children and 6 infants were administered orally with CFTM-PI granules at a dose level of 3 mg/kg at 30 minutes after meal, and serum concentrations and urinary excretion rates of CFTM were determined. Tmax in school children, younger children and infants were 2.8 +/- 0.3, 3.4 +/- 0.3 and 2.0 +/- 0.4 hours, respectively. Slightly earlier Tmax's were observed in infants than in other children. Cmax in school children, younger children and infants were 1.22 +/- 0.11, 1.03 +/- 0.12 and 0.94 +/- 0.15 micrograms/ml, respectively. It seemed slightly high in the older school children, younger children, infants. Although T 1/2 were nearly the same in all age groups, it seemed somewhat longer in school children than in others. Urinary excretion rates in school children, younger children and infants were 21.5 +/- 1.8, 19.3 +/- 2.0 and 7.6 +/- 0.1%, respectively. Obviously low excretion rates were observed in infants.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetic studies on oral antibiotics in pediatrics. V. A pharmacokinetic study on cefdinir in pediatrics]

A pharmacokinetic study was performed on cefdinir (CFDN, FK482) 5% fine granules for pediatric use, and pharmacokinetic parameters were calculated. 1. Twenty school children were administered orally a dose level of 3 mg/kg of CFDN fine granules either at 30 minutes before meal (14 children) or 30 minutes after meal (6 children). Plasma concentrations and urinary recovery rates of CFDN were measured. Tmax, Cmax, T 1/2 and urinary recovery rate (0-8 hours) following the administration before meal were 2.00 +/- 0.00 hours, 1.14 +/- 0.11 micrograms/ml, 1.63 +/- 0.14 hours and 23.68 +/- 2.92%, respectively, Tmax, Cmax, T1/2 and urinary recovery rate following the administration after meal were 3.67 +/- 0.33 hours, 0.71 +/- 0.06 micrograms/ml, 2.18 +/- 0.16 hours and 21.76 +/- 2.36%, respectively. Earlier Tmax and higher Cmax were observed when the drug was administered before meal than when administered after meal. There was no statistically significant difference between the 2 groups in urinary recovery rates. However, statistically significant difference was found between the 2 groups when the cross-over technique was used in 6 school children. Nineteen younger children (before meal) and 6 younger children (after meal) were administered with the drug in the same way, and several parameters were measured. Tmax, Cmax, T1/2 and urinary recovery rate following the administration before meal were 2.11 +/- 0.11 hours, 0.98 +/- 0.14 micrograms/ml, 1.71 +/- 0.23 hours and 23.60 +/- 1.72%, respectively, Tmax, Cmax, T1/2 and urinary recovery rate following the administration after meal were 3.33 +/- 0.42 hours, 0.47 +/- 0.14 micrograms/ml, 2.35 +/- 0.27 hours and 12.24 +/- 2.02%, respectively. Earlier Tmax, higher Cmax and higher urinary recovery rate were observed when the drug was administered before meal than when administered after meal. Seven infants (before meal) and 8 infants (after meal) were administered with the drug in the same way, and several parameters were measured. Tmax, Cmax, and T1/2 following the administration before meal were 4.00 +/- 0.62 hours, 0.61 +/- 0.13 micrograms/ml and 3.14 +/- 0.62 hours, respectively, Tmax, Cmax and T 1/2 following the administration after meal were 3.75 +/- 0.25 hours, 0.79 +/- 0.13 micrograms/ml and 2.44 +/- 0.42 hours, respectively. These was no statistically significant difference between the 2 groups. 2. Twenty one school children were administered orally with CFDN fine granules at 30 minutes before meal ata dose level of either 3 mg/kg (14 children) or 6 mg/kg (7 children). Plasma concentrations and urinary recovery rate of CFDN were measured.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetic study on oral antibiotics in pediatrics. III. A pharmacokinetic study on cefprozil in pediatrics]

The absorption and excretion were studied in the field of pediatrics, and pharmacokinetic analyses were performed. 1. Influence of food: Cefprozil (CFPZ, BMY-28100) was given to 6 school children in a before and after meal cross over design. With before meal administration, Tmax was 1.11 +/- 0.08 hours, Cmax was 5.08 +/- 0.27 micrograms/ml, T 1/2 was 0.77 +/- 0.09 hour, and urinary recovery rate (0-8 hours) was 55.2 +/- 4.7%. With after meal administration, these values were 1.31 +/- 0.04 hours, 3.98 +/- 0.38 micrograms/ml, 0.72 +/- 0.03 hour and 46.3 +/- 9.0%, respectively. A shorter Tmax value was, obtained higher Cmax and more or less higher urinary recovery rate when the drug was administered before meal, hence the food was considered to influence the absorption of the drug. 2. Dose effect: CFPZ was given on empty stomach to 6 school children in doses of 7.5 mg/kg and 15.0 mg/kg in the cross over design. With the lower dose Cmax was 6.19 +/- 0.36 micrograms/ml and AUC was 14.90 +/- 1.02 micrograms.hr/ml, and with the higher dose they were 12.38 +/- 1.29 micrograms/ml and 28.56 +/- 1.79 micrograms.hr/ml. Dose effects appeared to exist for CFPZ. A higher urinary recovery rate was obtained at the dosage of 7.5 mg/kg (82.1 +/- 6.4%) compared to the dosage of 15.0 mg/kg (51.1 +/- 7.1%). 3. Influence of age: CFPZ was given on empty stomach to 17 school children, 19 younger children and 5 infants. Tmax were 1.07 +/- 0.09, 1.06 +/- 0.07, and 1.40 +/- 0.09 hours, respectively for the 3 groups, hence significantly longer Tmax was observed in infants. Cmax were higher in older children and they were 5.62 +/- 0.38, 4.72 +/- 0.53 and 4.05 +/- 0.33 micrograms/ml, in the 3 age groups, respectively. T 1/2 were 0.73 +/- 0.04, 0.78 +/- 0.09 and 0.98 +/- 0.12 hour, respectively, it was longer in infants. The AUCs were not different among the 3 groups, but different urinary recovery rates were obtained with higher recovery in school children, with values of 64.1 +/- 4.3, 44.3 +/- 3.8 and 51.6 +/- 3.3%, respectively.     

Clinical studies on cefixime in pediatrics

Clinical usefulness of cefixime (CFIX), a new oral cephalosporin antibiotic, in pediatric field was investigated. The results obtained were summarized as follows. 1. The clinical efficacy of CFIX was investigated in a total of 138 children including 49 with upper respiratory tract infections (RTI), 22 with acute bronchitis, 18 with pneumonia, 19 with scarlet fever and 21 with urinary tract infections (UTI). 2. Clinical effectiveness was excellent in 58, good in 60, fair in 14 and poor in 3, with an overall efficacy rate of 87.4%. The efficacy rate classified according to types of infection were 85.7% in upper RTI, 89.5% in acute bronchitis, 94.4% in pneumonia, 78.9% in scarlet fever, and 90.5% in UTI. 3. Out of the suspected causative organisms, 43 strains of a total of 50 strains isolated were eradicated. The bacteriological eradication rate was 86.0%. (Haemophilus influenzae 100%, Haemophilus parainfluenzae 100%, Streptococcus pyogenes 88.5%, Escherichia coli 85.7%). 4. One hundred forty four children were analyzed for side effect. Side effects were observed in 2 children (1.4%) with diarrhea in 1 and anorexia in another. Abnormal laboratory test results were recorded in 4 children (3.3%). The above results suggest that CFIX is a very useful new oral cephalosporin for the treatment of bacterial infections in children.     

Clinical studies on cefixime in pediatrics

A clinical study of cefixime (CFIX), a new oral cephalosporin, was carried out to evaluate its therapeutic effectiveness on bacterial infections in children. CFIX was orally administered to 13 patients including 6 with upper respiratory tract infection (RTI), 3 with pneumonia, and 1 each with bronchitis, otitis media, skin abscess, and urinary tract infection (UTI). The daily dosage per kg bodyweight ranged from 5.1 to 17.4 mg (average: 8.7 mg), and was given in 2 or 3 divided doses per day for 3 to 10 days (average: 5.8 days). The clinical response was excellent in 4 (30.8%), good in 7 (53.8%) and poor in 2 (15.4%), with an overall efficacy rate of 84.6%. Bacteriological efficacy was good, and 6 of the 8 identified causative organisms were eradicated. Side effects were observed in 3 children, i.e., loose stool in 1 and transient elevations of GOT and GPT in 2. The above results suggest that CFIX is a useful new oral cephalosporin for the treatment of bacterial infections in children.     

Fundamental and clinical studies on cefixime in pediatrics

Bacteriological, pharmacokinetic, and clinical studies of cefixime (CFIX), a newly developed oral cephalosporin, was conducted in our pediatric department as outlined below. Bacteriology The prevalent MICs of CFIX by microbiological species, compared with those of the reference drugs, were detailed below. Against 16 strains of S. aureus, the MICs averaged 6.25 micrograms/ml, and were found to be nearly the same as the MICs of amoxicillin (AMPC) but higher than those of cephalexin (CEX) and cefaclor (CCL). For 4 strains of S. pyogenes, the MICs averaged 0.05 microgram/ml, and were higher than the MICs of AMPC but lower than those of CEX and CCL. Mean MICs of CFIX against other clinical isolates were lower than those of CEX, CCL, or AMPC; E. coli (20 strains), 3.13 micrograms/ml; K. pneumoniae (9), 0.10 microgram/ml; P. mirabilis (16), 0.025 microgram/ml; P. vulgaris (5), 0.10 microgram/ml; H. influenzae (11), 0.05 microgram/ml; and S. typhimurium (4), 0.10 microgram/ml. The MICs of CFIX against 10 strains of P. aeruginosa were distributed at and above 25 micrograms/ml, a range much lower than greater than or equal to 100 micrograms/ml for CEX, CCL, or AMPC. Pharmacokinetics The serum concentrations and urinary recovery were studied in 3 children ranging from age 7 to 13. They were given CFIX on empty stomach in 2 different single doses of 3 and 6 mg/kg in a cross-over design. Average serum CFIX concentrations were dose-dependent, as evidenced by the respective peak concentrations of 1.70 microgram/ml for a 3 mg/kg dosage and 2.72 micrograms/ml for 6 mg/kg, which were attained 4 hours after the administration of the drug. The average half-lives of CFIX in the serum were 3.09 hours and 3.11 hours, respectively, and the 12-hour serum concentrations were 0.32 microgram/ml and 0.77 microgram/ml, respectively, for the 2 different dose levels. The average 12-hour urinary recovery was 25.2% and 22.3%, respectively. Clinical study Clinical effectiveness, bacteriological effectiveness, and side effects were studied in 27 children with infection including 4 patients with acute pharyngitis, 13 with acute purulent tonsillitis, 5 with acute pneumonia, 3 with urinary tract infection, and 1 each with acute rhinitis and acute bronchitis. One child with acute pneumonia (Mycoplasma pneumonia) was excluded from the study. The therapeutic effectiveness was "excellent" in 21, "good" in 3, "fair" in 1, and "poor" in 1, with an effectiveness rate of 92.3%.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clinical studies of cefixime granules in pediatrics

A newly developed cephalosporin, cefixime (CFIX), was evaluated clinically in 35 pediatric patients. A pharmacokinetic study was also performed with 11 patients. CFIX was administered as granules. The pharmacokinetic study was conducted in 11 patients, each of 6 patients was given CFIX at a dose of 3 mg/kg and each of the remaining patients was given CFIX at 6 mg/kg. Serum concentrations of CFIX were measured at 2, 4, 6, 8 and 12 hours after dosing. Urinary concentrations of CFIX were measured for periods of 0-6 and 6-12 hours after dosing. CFIX was assayed by the disk method using E. coli ATCC 39188 as the test organism. The clinical evaluation was conducted in 35 children including 5 patients of acute tonsillitis, 10 of acute lacunar tonsillitis, 1 of purulent lymphadenitis, 1 of scarlet fever, 8 of acute bronchitis, 5 of pneumonia, 3 of urinary tract infections and 1 of paratyphoid B. One additional patient was included only in the evaluation of safety since he was suffering from Mycoplasma pneumonia. the patients were from 4 months to 8 years 2 months old and 11 of them were inpatients. Daily doses were from 6.0 to 13.5 mg/kg. After CFIX administration in doses of 3 mg/kg and 6 mg/kg, peak serum concentrations were 1.75 and 3.36 micrograms/ml, half-lives were 2.65 and 2.86 hours and urinary excretions rates up to 12 hours after dosing were 16.1 and 12.4%, respectively. Serum concentrations were dose dependent and the half-life was fairly long compared with other known oral cephalosporins. Clinical efficacies of CFIX in 34 patients were "excellent" in 25 children, "good" in 8 and "poor" in 1 with effectiveness rate of 97.1%. Twenty-two strains of causative organisms, including 6 strains of S. aureus, 3 of S. pyogenes, 2 of S. pneumoniae, 3 of E. coli, 5 of H. influenzae, 2 of H. parainfluenzae and 1 of S. paratyphi B, were isolated. After treatment all strains except 2 strains of S. aureus (one was unknown and the other was decreased), 1 strain of S. pneumoniae (unknown) and 1 strain of H. influenzae (unknown) were successfully eradicated but S. paratyphi B was proved again in feces 9 days after treatment. No adverse reaction was observed. Among 18 children who went through laboratory test, however, an elevation of eosinophile and elevations of GOT and GPT were observed in 2 children and 1 child, respectively.     

Fundamental and clinical studies of cefixime granules in pediatrics

Fundamental and clinical studies of cefixime (CFIX) granules, a new oral cephalosporin, were carried out with the following results: The MICs of CFIX against 234 clinical isolates were determined. Antibacterial activities of the drug against S. aureus, S. epidermidis and E. faecalis were weaker than those of conventional oral cephalosporins but antibacterial activities against Gram-negative bacteria were almost the same as those of cephem antibiotics of the Fujii's group 5. Peak serum concentrations of CFIX after oral doses of 3 and 6 mg/kg were, respectively, 1.51-4.86 micrograms/ml at 2-6 hours and 3.22-7.76 micrograms/ml at 4-8 hours. Serum concentrations of CFIX were dose-dependent in a patient given 3 and 6 mg/kg in a cross-over study. CFIX granules were administered mainly to children suffering from respiratory tract infection, otitis media and urinary tract infection at a dose of 3 mg/kg b.i.d. or t.i.d. for 3-27 days. The clinical responses to CFIX were excellent to good in 44 of the 50 children with infections, with an effectiveness rate of 88%. Thirty-five strains of the 40 clinical isolates were eradicated by the treatment with CFIX. The bacteriological eradication rate was 87.5%. Side effects observed were diarrhea and soft stool in 2 patients each, and elevated GOT X GPT and eosinophilia in 1 patient each. These symptoms and laboratory abnormalities disappeared on the day after the completion of therapy with CFIX. From the above results it has been concluded that CFIX is a useful and safe antibiotic for treating various bacterial infections in children.     

Pharmacokinetic and clinical studies on cefpirome in pediatrics

Cefpirome (CPR, HR 810), a new parenteral cephalosporin antibiotic, was studied for its pharmacokinetics, bacteriological and clinical effects in the field of pediatrics. 1. CPR was very active against Staphylococcus aureus, Staphylococcus epidermidis, Coagulase-negative staphylococci, Streptococcus pneumoniae among Gram-positive cocci. Antibacterial activities of CPR were also strong against Branhamella catarrhalis, Haemophilus influenzae, Escherichia coli, Salmonella sp., Klebsiella oxytoca, Enterobacter cloacae, Pseudomonas aeruginosa among Gram-negative rods. 2. The plasma concentration 15 minutes after a bolus intravenous injection of 20 mg/kg was 80.4 micrograms/ml, and the T 1/2 (beta) was 1.03 hours. Plasma concentrations after intravenous drip infusion over 30 minutes of 20 mg/kg and 25 mg/kg were 48.3 and 117 micrograms/ml at the end of infusion, and T 1/2 (beta) for these dosage were 1.14 and 1.45 hours. 3. The urinary recovery rates over 6 hours after administration were 45.2-63.9% for CPR. 4. Clinical efficacies of CPR were excellent in 31 patients and good in 30 patients with an efficacy rate of 98.4%. In bacteriological examinations, causative organisms were eradicated with an eradication rate of 95.7%. 5. As side effects, diarrhea was observed in 5 patients and loose stool in 1 patient with an incidence of 8.2%. Abnormal values were found in some patients in clinical laboratory tests for eosinophilia, thrombocytosis and an elevation of GOT, GPT and triglyceride. These findings indicate that CPR will be useful against bacterial infections in pediatrics.     

Clinical study on cefixime granules in the field of pediatrics

The absorption and excretion and clinical effectiveness of cefixime (CFIX) granules, a new oral cephalosporin, were studied with pediatric patients with tonsillitis and urinary tract infection (UTI). Peak serum concentrations in 3 children given orally a single dose of 3 mg/kg on fasting were 0.545 micrograms/ml at 2 hours in 1 patient, and 1.56 and 1.26 micrograms/ml at 4 hours in the other 2. The half-lives in the 3 patients were 3.21-3.42 hours, with an average of 3.29 hours. The urinary concentration during the first 6 hours was 36.5 micrograms/ml in 1 patient showing the low serum level, and the first 6-hour urinary recovery rate was 7.3%. In the other 2 patients, urinary concentrations and recovery rates up to 6 hours were 87 and 62 micrograms/ml, and 17.0 and 15.1%, respectively. The second 6-hour urinary concentrations and recovery rates were 35.5 and 20.8 micrograms/ml, and 12.7 and 8.8%, respectively. The urinary recovery rates up to 12 hours were 29.7 and 23.9%, respectively. CFIX was given orally to 19 children with 20 diseases in daily doses of 6.4-12.9 mg/kg in 2 or 3 divided portions for 3 to 12 days. Clinical evaluations were made on 18 diseases. Clinical effects of CFIX were excellent in 4, good in 7 and poor in 1 of the 12 patients with tonsillitis, and excellent in 5 and good in 1 of the 6 patients with UTI. The overall clinical effectiveness rate was 94.4%. No side effects were observed in any of the 19 patients. Hematological tests, showed slight elevation of blood platelet counts in 2 patients.(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.     

Pharmacokinetic and clinical studies of cefuzonam in pediatrics

Pharmacokinetic and clinical studies were conducted to evaluate cefuzonam (L-105, CZON), a new cephem type antibiotic, in the pediatric field. A total of 9 pediatric patients (2-14 years) was treated with intravenous injection of CZON: 4 cases with one shot of 20 mg/kg, 2 cases with one shot of 40 mg/kg and 3 cases with drip infusion over 1 hour of 40 mg/kg. CZON concentrations in serum and the excretion in urine were determined. Mean serum concentrations of CZON after one shot intravenous injection of 20 mg/kg were 49.0, 22.7, 9.03, 2.13, 0.37, and 0.09 micrograms/ml at 15, 30 minutes, 1, 2, 4 and 6 hours, respectively. With 40 mg/kg one shot intravenous injections, mean serum concentrations were 117.5, 68.0, 26.2, 8.80, 0.63 and 0.19 micrograms/ml at 15, 30 minutes, 1, 2, 4 and 6 hours, respectively. With 40 mg/kg intravenous drip infusions over 1 hour, mean concentrations were 57.1, 78.8, 12.9, 1.12 and 0.23 micrograms/ml at 30 minutes, 1, 2, 4 and 6 hours, respectively. Mean half-lives were 0.69 hour for 20 mg/kg one shot injections, 0.44 hour for 40 mg/kg one shot injections, and 0.58 hour for 40 mg/kg 1 hour drip infusions. Urinary recovery rates in 6 hour after administration were 70.8% (mean) for the 20 mg/kg one shot injection, 44.1% (1 case) for the 40 mg/kg one shot injection, and 60.0% (mean) for the 40 mg/kg 1 hour drip infusion. CZON was administered in 26 cases of pediatric infections, and the clinical efficacy, antibacterial activity, and side effects were evaluated. Of the 26 cases 2 were excluded for the reason of not having bacterial infection, and the remaining 24 cases were assessed. Included in the 24 cases were 16 cases of acute pneumonia, 2 cases of acute purulent lymphadenitis, and 1 case each of acute bronchitis, acute purulent otitis media, acute apical periodontitis, staphylococcal scalded skin syndrome (SSSS), acute pyelonephritis, and acute enteritis. Clinical efficacy evaluation showed 19 excellent cases and 5 good cases, with an efficacy rate of 100%. Bacteriologically, Staphylococcus aureus 1 strain, Streptococcus pneumoniae 1 strain, beta-Streptococcus 1 strain, Haemophilus influenzae 10 strains, Haemophilus parainfluenzae 1 strain, Proteus mirabilis 1 strain, and Campylobacter jejuni 1 strain were determined or assumed as pathogens, but all of them were eradicated.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clinical and pharmacokinetic studies on sultamicillin fine granules in pediatrics

Sultamicillin (SBTPC) is a mutual prodrug of sulbactam (SBT) and ampicillin (ABPC). A study has been performed to evaluate pharmacokinetic properties and clinical usefulness of SBTPC fine granules in the treatment of pediatric infections. After an oral dose of 5-15 mg/kg of SBTPC fine granules, peak serum concentrations of ABPC and SBT were 1.18-3.26 micrograms/ml and 0.97-3.05 micrograms/ml, respectively at 1 hour. Serum half-lives for elimination (T 1/2 (beta] of ABPC and SBT were 0.83-1.83 hours and 0.94-1.71 hours, respectively. Serum concentrations of ABPC at 1-6 hours after an oral administration of SBTPC fine granules were similar to those of SBT. Serum concentrations of ABPC and SBT were proportional to dose levels of SBTPC fine granules. Following oral administrations of 5-15 mg/kg, 33.9-64.8% of ABPC and 38.1-76.6% of SBT were recovered in urine in 6 hours. SBTPC fine granules were administered in a daily dose of approximately 30 mg/kg divided into 3 doses to 14 pediatric patients with bacterial infections. All 14 were cured with 11 excellent and 3 good clinical response to this drug. Microbiological eradication was obtained in 85.7%. beta-Lactamase-producing ABPC-resistant strains were eradicated. Adverse effects including laboratory test values that may be attributed to the administration of SBTPC fine granules were not observed except a treatment episode of diarrhea in 1 patient.     

Pharmacokinetics and clinical effects of cefixime in pediatrics

Pharmacokinetics and clinical effects of cefixime (CFIX), a new oral cephalosporin antibiotic, in pediatric field were investigated. The result obtained were summarized as follows. CFIX (5% granules) was given to each of 5 children twice in a single dose of 1.5 or 3.0 mg/kg in a cross-over trial. The mean peak serum concentration of CFIX was 0.64 micrograms/ml at 4 hours after given the dose of 1.5 mg/kg and 1.15 micrograms/ml at 4 hours after the dose of 3.0 mg/kg. The mean half-life and the mean AUC values were 2.72 hours and 4.10 micrograms X hr/ml, respectively after the dose of 1.5 mg/kg, and 2.77 hours and 8.26 micrograms X hr/ml after the dose of 3.0 mg/kg. The urinary recovery was investigated in 5 children after the dose of CFIX of 1.5 mg/kg and in 4 children after the dose of 3.0 mg/kg. The mean peak urinary concentrations of CFIX and the mean 12-hour urinary recovery rates were 10.6-67.9 micrograms/ml at 2-10 hours and 15.7% after the dose of 1.5 mg/kg, and were and were 6.16-230 micrograms/ml at 2-8 hours and 18.9% after the dose of 3.0 mg/kg, respectively. CFIX was given to 6 children twice in a single dose of 50 mg either in the form of 5% granules or in capsules in a cross-over trial. The mean peak serum concentrations, half-life and AUC values were 1.26 micrograms/ml at 4 hours, 3.09 hours and 9.63 micrograms X hr/ml, respectively after the dose of 50 mg CFIX in 5% granules, and were 1.16 micrograms/ml at 4 hours, 2.87 hours, and 7.82 micrograms X hr/ml, respectively after the dose of 50 mg in capsules. The urinary recovery was investigated in 5 children. The mean peak urinary concentrations and the mean 12-hour urinary recovery rates were 19.1-114 micrograms/ml at 4-10 hours and 15.7%, respectively after the dose of 50 mg in 5% granules, and were 8.16-89.0 micrograms/ml at 4-10 hours and 11.3%, respectively after the dose of 50 mg in capsules. Clinical efficacy of CFIX was investigated in a total of 26 children including 2 with tonsillitis, 2 with acute bronchitis, 2 with scarlet fever and 20 with urinary tract infection. Each of children were given orally a dose of 2.6 mg/kg CFIX 2-3 times a day for 11 days in average.(ABSTRACT TRUNCATED AT 400 WORDS)     

Population pharmacokinetic studies in pediatrics: Issues in design and analysis

The current review addresses the following 3 frequently encountered challenges in the design and analysis of population pharmacokinetic studies in pediatrics: (1) body size adjustments during the development of pharmacostatistical models, (2) design and validation of limited sampling strategies, and (3) the integration of historical priors in data analysis and trial simulation. Size adjustments with empiric approaches based on body weight or body surface area have frequently proven as a pragmatic tool to overcome large size differences in a pediatric study population. Allometric size adjustments, however, provide a more mechanistic, physiologically based approach that, if used a priori, allows delineation of the effect of size from that of other covariates that show a high degree of collinearity. The frequent lack of dense data sets in pediatric clinical pharmacology because of ethical and logistic constraints in study design can be overcome with the application of D-optimality-based limited sampling schemes in combination with Bayesian and nonlinear mixed-effects modeling approaches. Empirically based dose selection and clinical trial designs for pediatric clinical pharmacology studies can be improved by applying clinical trial simulation techniques, especially if they integrate adult and pediatric in vitro and/or in vivo data as historic priors. Although integration of these concepts and techniques in population pharmacokinetic analyses is not only limited to pediatric research, their application allows researchers to overcome some major hurdles frequently encountered in pharmacokinetic studies in pediatrics and, thus, provides the basis for additional clinical pharmacology research in this previously insufficiently studied fraction of the general population.     

Pharmacokinetic and bacteriological studies on sulbactam/ampicillin in the field of pediatrics

Pharmacokinetic and bacteriological studies were carried out on sulbactam/ampicillin (SBT/ABPC) in the field of pediatrics. The results obtained are summarized as follows: 1. A total of 248 clinical isolates were employed to determine minimum inhibitory concentrations (MIC) of SBT/ABPC against various bacterial species. SBT/ABPC showed stronger antibacterial activity against Gram-positive organisms than against Gram-negative rods. 2. The peak serum level of ABPC was about twice as high as that of SBT, and serum levels of ABPC and SBT declined with time. Both drugs showed almost the same trend of changes in concentrations. The half-lives of both drugs were about 1 hour. 3. The urinary recovery rates over 6 hours after administration were 52-80% for ABPC and 70-73% for SBT. 4. The effect of SBT/ABPC on coagulation system was examined. No case showed changes in PT, APTT, TT and HPT before and after administration of SBT/ABPC. Platelet aggregation during administration of SBT/ABPC was slightly faster than that before administration, suggesting that SBT/ABPC had no effect on platelet aggregation. Generally speaking, it seemed that SBT/ABPC was a safe antibiotic for bleeding. 5. The effect of SBT/ABPC on the intestinal bacterial flora in experimental animals was examined. Escherichia coli, Enterococcus faecalis, Bacteroides fragilis and Bifidobacterium breve were reduced after administration of SBT/ABPC, suggesting that the intestinal bacterial flora was affected by the administration of SBT/ABPC more greatly than by the administration of ABPC alone. In a similar investigation being made with clinical cases, both aerobes and anaerobes showed great changes. Concentrations of the drugs in feces increased with increasing dosage, resulting in greater changes of the intestinal bacterial flora. Thus, the total number of aerobes and anaerobes was reduced. No diarrhea was observed in any subjects examined. From the above results, it appeared that SBT/ABPC was a safe and useful antibiotic for various bacterial infections in the field of pediatrics.     

Clinical and pharmacokinetic studies on intravenous administration of sulbactam/ampicillin in pediatrics

Intravenous administration of sulbactam/ampicillin (SBT/ABPC) was evaluated in pediatric patients. The serum half-lives of both ABPC and SBT were approximately 1 hour following the intravenous injection or intravenous drip infusion of 20-35 mg/kg, and 30-50% of ABPC and 30-70% of SBT were recovered in the urine 6 hours. Cerebrospinal fluid concentrations of ABPC and SBT were 0.76 and 0.68 micrograms/ml, respectively, at 1 hour after intravenous drip infusion of the 58 mg/kg, and concentration ratios of the drugs in cerebrospinal fluid/serum were 6.39 and 5.71%, respectively. Thirty-four pediatric patients were treated with intravenous drip infusion of SBT/ABPC in doses ranging from 54 to 150 mg/kg divided into 3 times a day. The rate of clinical efficacy was 93.5% and the bacterial elimination rate was 92.3%. The synergistic activity of sulbactam with ampicillin was demonstrated against beta-lactamase-producing Staphylococcus aureus and Haemophilus influenzae isolated from patients in the present study. The side effects of SBT/ABPC were observed in 6 patients (5 diarrheas; 1 diarrhea with vomiting) out of 34 patients administered. Eosinophilia (2 patients) and a slight elevation of GOT (1 patient), GPT and LDH (1 patient) were observed. The tolerance to the therapy, however, was good.     

Pharmacokinetic, bacteriological and clinical studies on cefpodoxime proxetil in the field of pediatrics

Pharmacokinetic, bacteriological and clinical studies on cefpodoxime proxetil (CPDX-PR, CS-807), a newly developed oral cephem, were carried out in the treatment of infectious diseases in the field of pediatrics. 1. Since CPDX demonstrates very powerful antimicrobial actions against such Gram-negative bacilli as Escherichia coli, Salmonella sp., Klebsiella pneumoniae and Serratia sp., such Gram-positive cocci as Streptococcus pyogenes and Streptococcus pneumoniae, and beta-lactamase producing Branhamella catarrhalis and Haemophilus influenzae, this drug was thought to be useful for the treatment of pediatric infectious diseases when main causative bacteria in the field of pediatrics were taken into account. 2. When changes in blood and urine concentrations of CPDX following the administration of this drug at 3.7 mg/kg before meal were determined, Cmax and T1/2 were found to be 2.98 micrograms/ml at 2-hour and 1.73 hours, respectively; an urinary excretion rate in the first 6 hours and a maximum urine concentration were 32.5% and 52 micrograms/ml, respectively. 3. Clinically, 8 of 8 patients with the upper respiratory tract infections (100%), 28 of 29 patients with bronchitis and/or pneumonia (96.6%), 3 of 4 patients with otitis media (75%), 2 of 2 patients with sinusitis (100%), 3 of 3 patients with the skin soft tissue infections (100%), 1 of 1 patient with bacterial enteritis (100%) and 11 of 14 patients with urinary tract infections (78.6%) responded well to the treatment with CPDX-PR, showing a 91.8% efficacy rate in all the patients treated. 4. Bacteriologically, Staphylococcus aureus, Staphylococcus epidermidis, S. pyogenes, S. pneumoniae, E. faecalis, B. catarrhalis, H. influenzae, E. coli and Salmonella typhimurium were all eradicated from 5, 1, 4, 6, 1, 5, 5, 11 and 1 patient, respectively. An eradication rate in all the patients examined was 97.5% (39/40). 5. Gastrointestinal symptoms appeared as side effects in 2 of 71 patients (vomiting in 1 and diarrhea in 1), hence, an incidence of side effects was 2.8% (2/71). As for abnormal laboratory findings, eosinophilia, thrombocytosis and increases in GOT and GPT were observed in 3 of 39 patients examined (7.7%), 1 of 39 patients (2.6%) and 2 of 34 patients (5.9%), respectively. In addition, we also examined the effect of the drug on the hemostatic system, but found no changes upon the treatment. Based on these results, it appeared that CPDX-PR was a useful and safe drug in treatment of infectious diseases in the field of pediatrics when administered 2-3 times a day at a dose of 3-6 mg/kg.     

Pharmacokinetic and metabolic studies of vinpocetine on dogs. I. Pharmacokinetics

The pharmacokinetics of tritiated vinpocetine has been studied on dogs. The drug, when administered orally, was readily absorbed from the gastrointestinal tract (T1/2 0.3 h) and underwent similarly fast distribution (T1/2 0.8 h) in the organism. The mean value of the elimination half-life was 8.2 h. Approx. 75% of the administered radioactivity was excreted with urine and feces within 72 h. The pharmacokinetics of the intravenously administered, labelled compound showed that a similarly rapid distribution but a somewhat slower elimination took place. Fecal and urinary excretion of radioactivity applied amounted to about 82%. Investigation of the distribution of radioactivity between plasma and blood cells revealed that the radioactivity content did not bind to the cellular fraction of the blood. Pharmacokinetic studies of the same design in the literature allowed us to make some comparison between dogs, rats and humans in respect to the kinetic behavior of labelled vinpocetine.     

Pharmacokinetic and clinical studies on cefpodoxime proxetil dry syrup in the field of pediatrics

Cefpodoxime proxetil (CPDX-PR, CS-807) is a new oral cephem derivative drug in which carboxylic acid was esterified to the 4-position of CPDX (oxime type cephem antibiotic). CPDX-PR is hydrolyzed mainly with esterase in intestinal wall and CPDX exists as an active form in body fluid. While there are numerous study reports using CPDX-PR in tablet forms in Japan, the dry syrup formula for pediatric use was newly developed. The dry syrup of CPDX-PR was orally administered 20 minutes after meal to the 6 boys of ages from 8 years and 1 month to 10 years and 10 months, with doses of 3 and 6 mg/kg, respectively, for 3 cases each. Serum concentrations and urinary concentrations and recovery rate of the drug were investigated. In addition to the above, the clinical and bacteriological studies were performed in a total of 105 cases consisting of children with ages ranging from 2 months to 11 years and 8 months, upon administering an average dose of 3.4 mg/kg, 3 to 4 times per day (96 cases of 3 times and 9 cases of 4 times). The 105 cases included 13 cases of pharyngitis, 21 cases of tonsillitis, 4 cases of acute bronchitis, 6 cases of pneumonia, 1 case of pleurisy, 13 cases of scarlet fever, 41 cases of urinary tract infection, 3 cases of posthitis and 3 cases of bacillary dysentery. Drug sensitivity test was performed for the following strains: (i) Strains retained by our department; 52 strains of Streptococcus pyogenes, 18 strains of Streptococcus agalactiae, and 11 strains of Bordetella pertussis, and (ii) strains isolated from cases to which CPDX-PR was administered; 2 strains of Staphylococcus aureus, 8 strains of S. pyogenes, 2 strains of Haemophilus influenzae, 10 strains of Escherichia coli, and 1 strain of Proteus mirabilis. Drug sensitivities of the strains retained by our department were tested with the inoculum sizes of 10(8) and 10(6) cfu/ml for R-3746 (Na-salt of CPDX), cefaclor (CCL), cephalexin (CEX), amoxicillin (AMPC), and methicillin (DMPPC), and those against strains separated from the cases to which CPDX-PR was administered were tested with the same inoculum sizes for R-3746, CCL, CEX, cefadroxil, ampicillin (ABPC), DMPPC and cloxacillin (MCIPC). Adverse reactions and abnormal clinical laboratory test results were also examined.(ABSTRACT TRUNCATED AT 400 WORDS)