Diffuse pachygyria with cerebellar hypoplasia: a milder form of microlissencephaly or a new genetic syndrome?

We report on 2 families with diffuse pachygyria and cerebellar hypoplasia, who presented hypotonia, ataxia, seizures, and developmental delay since infancy. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed decreased gyral formation in the cerebral cortex and marked hypoplasia in the cerebellum. Cerebellar hypoplasia is often associated with type 2 lissencephaly; however, our cases showed no polymicrogyria, and their clinical findings were quite mild compared with those of microlissencephaly. Their characteristic phenotype suggested a new genetic syndrome, which was possibly inherited as an autosomal recessive trait.

Characterization of mutant holocarboxylase synthetase (HCS): a Km for biotin was not elevated in a patient with HCS deficiency.

Holocarboxylase synthetase (HCS) is an essential enzyme for the biotinylation of several mammalian carboxylases. A deficiency of HCS is accountable for early onset biotin-responsive multiple carboxylase deficiency. To address the mechanism of biotin responsiveness, we analyzed the kinetic properties of the previously identified mutant, L237P, and another mutant, V550M, described in this report. The V550M mutant contains a G to A transition at position 1935, which is within the putative biotin binding site, whereas the mutation in L237P occurs outside the biotin binding site. Km and Vmax values for the mutant proteins were determined by overexpressing cDNAs encoding the mutants in transformed fibroblasts from an HCS-deficient patient. Enzyme activity assays were performed using apo-carboxyl carrier protein as a substrate. A Km for biotin that was larger than the value found for the wild-type cDNA was observed in fibroblasts transfected with the V550M cDNA, but not the L237P cDNA. The Vmax for the expressed L237P cDNA was 4.3% of that observed for the wild-type cDNA. Biotin-responsiveness in the patient with the L237P mutation was neither due to an increased affinity for biotin nor a restoration of stability of the mutant by biotin treatment. A new mechanism of biotin responsiveness in HCS deficiency is presented.

[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.

[Pharmacokinetic and clinical studies with imipenem/cilastatin sodium in neonates].

Pharmacokinetic and clinical evaluations of imipenem/cilastatin sodium (IPM/CS) were carried out in neonates. The following results were obtained: 1. The plasma concentrations of IPM/CS were determined upon doses of 10 mg/10 mg/kg and 20 mg/20 mg/kg administered using 30- and 60-minute drip infusion, respectively. Peak concentrations of IPM/CS were 19.0-34.7 micrograms/ml/32.6-73.4 micrograms/ml, respectively, at the end of the drip infusion. Plasma half-lives of IPM and CS were 1.4-1.6 hours and 1.7-2.1 hours, respectively. 2. Over a period of 6-8.5 hours, urinary excretions of IPM and CS totaled 19.8-42.7% and 46.9-89.3% of the dose administered, respectively. 3. Clinical responses to IPM/CS were excellent in 4 patients, good in 8 patients and unknown in 1 patient. 4. No side effect was observed except for a platelet increase in 2 patients. From the above results, it has been concluded that IPM/CS is an effective and safe drug in the treatment of neonatal infections.

[Pharmacokinetic and clinical studies of ceftizoxime in newborn infants].

Pharmacokinetic and clinical studies of ceftizoxime (CZX) were performed in infants given intravenously. The obtained results are summarized as follows. 1. Serum concentrations of CZX in 2 and 3 day-old mature infants given 20 mg/kg by one shot intravenous injection peaked at 49.0 and 57.9 micrograms/ml in 1 hour and decreased to 14.4 and 24.9 micrograms/ml in 8 hours after dosing, respectively. Half-lives were 3.9 and 5.6 hours, respectively. In 5 day-old or older mature infants, peak serum levels ranged from 20.9 to 38.0 micrograms/ml at 1 hour after the injection. Levels of CZX at 8 hours after injection were 1.31 to 7.32 micrograms/ml. Half-lives were 1.6-3.0 hours in all the infants except one. 2. In a 3 day-old premature infant given the same dose by a bolus intravenous injection, the serum level peaked at 45.7 micrograms/ml in 1 hour after the injection. The level at 8 hours after injection was 15.7 micrograms/ml. The half-life was 4.2 hours. In 5-15 day-old premature infants, half-lives were 2.3-3.1 hours in all the infants except one. 3. Serum concentrations of CZX in 1 and 2 day-old infants given 20 mg/kg by intravenous drip infusion peaked at 49.4 to 115.0 micrograms/ml in 1 hour after dosing. Half-lives were rather long, 4.0 and 5.1 hours, in the 2 infants. 4. Peak serum levels and half-lives tended to be lower and shorter in 5 day-old or older ones than in the 3 day-old or younger infants. 5. No changes in the serum concentration were observed even after dosing with 20 mg/kg of continuous one shot intravenous injection. 6. Urinary recovery rates during the first 8 hours (one is 6 hours, two is 9 hours) after 20 mg/kg intravenous bolus injection of CZX tended to be lower in 3 day-old or younger infants than in 5 day-old or older infants. 7. Eleven infants with various bacterial infections were given CZX by intravenous bolus injection or drip infusion. Dosage of CZX used in the present study were 36-148 mg/kg/day in 2-3 divided doses. Duration of treatment ranged from 3 to 12 days. Clinical efficacy of CZX was excellent or good in all the infants with acute bronchitis, acute pneumonia, suspected sepsis infected in uterine, acute otitis media, cellulitis, meningitis caused by Klebsiella pneumoniae and Escherichia coli, acute urinary tract infection and periproctic abscess except 1 case of acute bronchitis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Bacteriological, pharmacokinetic and clinical studies of a rokitamycin syrup in pediatrics].

Rokitamycin (RKM) dry syrup was administered to a group of pediatric patients. The results obtained are summarized as follows. 1. Of the recent isolates of Streptococcus pyogenes, fewer strains were highly resistant to RKM than to josamycin (JM), midecamycin (MDM), erythromycin and lincomycin. Also, macrolides (MLs)-resistant strains proved to be susceptible to RKM. 2. Recent isolates of Staphylococcus aureus, Streptococcus agalactiae, group G Streptococci, S. pyogenes, Streptococcus pneumoniae and Haemophilus influenzae were more susceptible to RKM than to midecamycin acetate and JM. Oral administrations of 10-15 mg/kg of the drug were followed by its peak concentrations of 0.07-0.77 micrograms/ml in the blood at 30 minutes in many patients, and by an undetectable level at 6 hours also in many of them. T1/2 values were 1.2-2.6 hours, and first 6-hour urinary excretion rates were 1.26-1.74%. 3. Fifty-two patients with acute upper and lower respiratory tract infections, Campylobacter enteritis, etc. were treated with RKM at about 20-40 mg/kg daily for 4-14 days, with an overall efficacy rate of 88.5%. 4. An eradication rate of 81.4% was achieved for 43 strains of 7 species isolated from the patients. 5. No abnormal laboratory test values were observed after treatment with drug 4 approximately 14 days. A side effect, stomach discomfort, was observed in 1 patient.

[Evaluation on ceftriaxone administered intravenously in neonates].

Ceftriaxone (CTRX) was clinically evaluated and its pharmacokinetics studied in neonates. The results obtained are summarized below. 1. Blood levels of CTRX at 8 to 12 hours after intravenous injection with a single dose of 10 to 20 mg/kg ranged from 14.9 to 32.8 micrograms/ml, while T1/2 ranged from 8.2 to 24.8 hours. 2. Blood levels of CTRX at 11 hours after the completion of drip infusion which lasted one hour with a dose level 10 to 20 mg/kg, ranged from 10.6 to 25.0 micrograms/ml, while T1/2 was 5.4 to 22.8 hours. 3. Multiple intravenous administrations were given to premature infants, but blood levels did not show evidence of drug accumulation. 4. Urinary excretion in 6 hours after an intravenous injection or a drip infusion with 10 approximately 20 mg/kg of CTRX ranged from 13.8 to 58.5% of the dosage. 5. The subjects in this study were 9 neonates with suspected sepsis, pneumonia, Staphylococcus epidermidis or Staphylococcus aureus infections (sepsis, staphylococcal scalded skin syndrome, pneumonia), acute bronchitis or meconium aspiration syndrome. Efficacies CTRX were excellent or good in all these cases administered in a daily dose of 19.5 to 41.6 mg/kg for 4 to 11 days. 6. No general side effects or abnormalities were observed in blood count, or hepatic or renal function.

[Studies on the intravenous administration of amikacin to neonates].

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

[Evaluation of cefuzonam in the pediatric field].

Cefuzonam (L-105, CZON) was studied in pediatric infections. A summary of the results it as follows: For recently isolated Staphylococcus aureus strains, Peak MICs of CZON were distributed between 0.39 and 0.78 micrograms/ml showing a greater susceptibility of S. aureus to CZON than to cefoperazone (CPZ), latamoxef (LMOX), and cefmenoxime (CMX). Peak MICs of CZON for Escherichia coli were 0.10-0.20 micrograms/ml, similar to those of CPZ, LMOX, and CMX. Ampicillin (ABPC)-resistant strains were also susceptible to CZON. MICs for Salmonella were similar to those for E. coli. Peak MICs of CZON for Vibrio parahaemolyticus were 0.20-0.39 micrograms/ml. The susceptibility of the bacteria to CZON was far greater than to ABPC, and was similar to CPZ, LMOX, and CMX. With 20 mg/kg drip infusion, serum concentrations reached their peaks at the end of administration with values of 20.6-68.7 micrograms/ml, which decreased to 0.43-1.70 micrograms/ml after 2 hours. Half-lives of CZON in serum were 0.68-1.2 hours. With 50 mg/kg drip infusion, serum concentrations reached their peaks at the end of administration with levels of 69.0-82.0 micrograms/ml, and at after 2 hours 1.85-3.45 micrograms/ml. Thus, an apparent dose response was observed. Half-lives of CZON in serum were 0.63-0.99 hours. Urinary recovery rates in 6 hours were 39.9-80.5%. A total of 44 cases of 10 different types of acute pediatric infections was treated by CZON intravenous drip infusion as the main therapeutic procedure. The efficacy rate was 93.2%, and the compound was effective on purulent infections, acute urinary tract infection, etc. with pathogens such as ABPC-resistant S. aureus, E. coli, and Enterococcus faecalis. Dosage levels per day were 50 to 80 mg/kg in most cases. In infections with S. aureus (8 strains), Streptococcus pneumoniae (3 strains), E. faecalis (1 strain), Haemophilus parahaemolyticus (1 strain), Haemophilus parainfluenzae (2 strains), Haemophilus influenzae (11 strains), Bordetella pertussis (1 strain), E. coli (3 strains), a total of 30 strains, bacterial elimination was noted with an exception of 1 strain of S. aureus. The compound was used for 4 to 15 days, but side effects observed clinically were only 1 case of diarrhea and 1 case of thrombocytosis.

The effects of mechanical vibration on cardiac morphogenesis in the stage 14 chick embryo.

The primitive cardiac loop of the stage 14 (Hamburger and Hamilton) chick embryo was subjected to brief vibratory stimuli that resulted in a broad spectrum of cardiovascular malformations. During the 17th day of incubation, both survival and anomaly rates were evaluated. Compared with control embryos (92%), vibration elicited mortality (75%) that was statistically highly significant (p less than 0.001). In addition, the anomaly rate (94%) among surviving embryos was also highly significant (p less than 0.001) relative to controls. Defects included straddling AV valves, variable sizes of VSD and DORV. Several possible explanations are presented concerning the etiology of these vibration-induced malformations.

[Study on intravenous drip infusion therapy of cefotiam in neonates and infants].

Intravenous drip infusion (d.i.) of cefotiam (CTM) in neonates and infants produced the following pharmacokinetic and clinical results: In a 2 and 3 day-old neonates group, blood concentrations at 1 and 5 hours after intravenous drip infusion of 20 mg/kg of CTM were 33.0 micrograms/ml and 12.3 micrograms/ml, respectively. Thus high blood CTM levels were maintained in these cases. In a 4 day-old neonate, blood concentrations after 1 and 6 hours were 20.5 micrograms/ml and 5.8 micrograms/ml. respectively. In a 8-13 day-old neonates group, blood levels after 1 and 6 hours were 12.2-18.5 micrograms/ml and 0.7-2.4 micrograms/ml, respectively. Compared to the corresponding values in the 2 and 3 day-old neonates, the blood CTM levels in this group were low. Half-lives of CTM in the blood were 1.8-2.7 hours, 2.1 hours, 1.1-1.7 hours and 0.7 hour, in 2-3 day-old neonates, 4 day-old neonate, 8-13 day-old neonates and a 45 day-old infant, respectively. Half-lives tended to become shorter with increasing age. The 6-hour urinary recoveries ranged between 20.3 and 62.3%. Transport of the drug into the spinal fluid was also observed. The CTM was very effective in the treatment of 6 patients suffering from suppurative meningitis, septicemia, bronchopneumonia or UTI with ampicillin-resistant E. coli. The daily dose ranged between 41 and 175 mg/kg. The duration of the treatment was 5 to 18 days, with total doses of 0.72 to 16.25 g. In only one case, a transient eosinophilia was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

[Fundamental and clinical evaluations of ceftazidime in neonates].

Ceftazidime (CAZ) intravenous injection was evaluated from fundamental and clinical aspects in neonates, and the results obtained are summarized below. Following a 60-minute intravenous drip infusion of CAZ at 10 mg/kg, the peak serum level was 19.8 micrograms/ml at 30 minutes after the completion of the infusion(half-life: 2.75 hours). Following 30 to 60-minute intravenous drip infusions of CAZ at 20 mg/kg, the mean peak serum levels of CAZ were 33.1-33.0 micrograms/ml. Mean levels at 6 hours were 5.2-6.7 micrograms/ml (half-life: 1.6-4.1 hours). Following 30 to 60-minute intravenous drip infusions of CAZ at 25-30 mg/kg, peak serum levels were 51.7-64.6 micrograms/ml (half-life: 1.6-2.05 hours). Dose response relationship was clearly observed in peak serum levels after intravenous drip infusion, and half-lives of serum CAZ levels in neonates aged 0-10 days tended to be longer than those in infants. Following intravenous administration of CAZ at 20-30 mg/kg, urinary excretion rates during the first 6 hours were 18.7-66.5%, and the rates were low in neonates compared to those in infants and children. Following a 60-minute intravenous drip infusion of CAZ at 28.7 mg/kg, the cerebrospinal fluid level was 5.0 micrograms/ml at 3 hours, the ratio of cerebrospinal fluid level to serum level was 22.5%. Eleven neonates were subjected to the present study. Clinical efficacy of CAZ was excellent in sepsis caused by A. anitratus, which showed higher sensitivity to CAZ compared with other cephem antibiotics of the third generation. In all of the other cases, including those of pertussis and acute urinary tract infections and in the prophylaxis of amniotic infection, clinical efficacy of CAZ was excellent or good. S. epidermidis, E. coli and A. anitratus, identified from cultures of pharynx, urine or blood, were rapidly eliminated during the CAZ treatment. Doses of CAZ used in the present study were 29-133 mg/kg/day, mostly in the range of 40-60 mg/kg/day. Durations of treatment ranged from 3 to 10 days. Neither systemic nor local adverse effect was observed, nor was any abnormality observed in laboratory findings.

[Fundamental and clinical studies with imipenem/cilastatin sodium, a new carbapenem antibiotic, in the field of pediatrics].

Fundamental and clinical evaluations of imipenem/cilastatin sodium (MK-0787/MK-0791) were carried out in pediatric patients. The following results were obtained: After intravenous drip infusion of single doses of 10 mg/10 mg/kg to 20 mg/20 mg/kg of MK-0787/MK-0791 in children, peak plasma levels of MK-0787 ranged from 32.0 to 82.0 micrograms/ml at the end of the infusion. The half-life was 49.9 to 64.0 minutes. The cumulative urinary recovery at 6 to 7 hours after the 1 hour drip infusion ranged from 65.5 to 88.9%. Fecal levels of MK-0787 were 4.2 and 23.1 micrograms/g at 6 hours after a 30-minute intravenous drip infusion of 200 mg/200 mg of MK-0787/MK-0791. MK-0787/MK-0791 was administered by intravenous drip infusion to patients with purulent meningitis. Penetration into the cerebrospinal fluid was satisfactory, as were the clinical responses. MK-0787/MK-0791 was administered clinically in doses of 30 mg/30 mg/kg/day to 200 mg/200 mg/kg/day by intravenous drip infusion 3 or 4 times a day for 3 to 22 days to 26 patients with acute pediatric infections. The clinical response was excellent in 18 patients and good in 8 patients. Eradication occurred with 16 isolates; only two strains of Salmonella-B were not eradicated. Anorexia in 1 patient was the only clinical adverse effect reported, and the only adverse effects found in laboratory tests were eosinophilia and thrombocytosis in 1 patient, respectively, and elevation of the S-GOT and S-GPT in 1 patient.

[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 aztreonam in the field of pediatric].

The fundamental and clinical studies of aztreonam (AZT) were performed. The results were as follows: The MICs of AZT for E. coli and Salmonella sp. which were recently isolated in the pediatric field were less than 0.78 micrograms/ml. AZT also was effective against ABPC/PIPC-resistant bacteria. The MIC of AZT for V. parahaemolyticus was less than 1.56 micrograms/ml. The peak serum levels of AZT which were occurred just after the 1 hour drip infusion of 10-30 mg/kg were 60.5-136.8 micrograms/ml, and at 6 hours after infusion the serum levels were 1.3-6.1 micrograms/ml; therefore, the dose response was proved. The mean half-lives (T 1/2) were between 1.21 and 1.36 hours. The excretion rates in urine up to 6 hours after intravenous drip infusion were between 32.7 and 77.5%. The ratio of the cerebrospinal fluid concentration to serum in the child with purulent meningitis was 3.5% at 1 hour after the intravenous injection at the dose of 69 mg/kg, and the ratios of the subdural fluid levels to serum were 31.3-37.5%. The levels of AZT into the feces by the multiple dosage were 0-840 micrograms/g. Twenty-five pediatric patients with acute infections had been treated by intravenous injection or drip infusion at the doses of 49-120 mg/kg/day (almost 50-100 mg/kg/day) for 4 to 13 days. The efficacy rate of excellent + good was 84% and that of excellent + good + fair was 96%. The efficacy rate of excellent + good was 100% in all cases with upper/lower respiratory tract infection, bronchopneumonia, and acute urinary tract infection caused by Gram-negative rods. The clinical efficacy was observed in all cases with acute bacterial enteritis. Although AZT was clinically effective against Salmonella enteritis, bacteriological efficacy on the causative organisms was not observed in some cases. Although AZT was bacteriologically effective in 1 patient with typhoid, it did not alleviated fever. AZT showed activity to 9 strains isolated from the culture of throat swab, urine and feces. No side effects were clinically observed in all cases, while slight elevations of laboratory findings were observed in 4 cases.

[Fundamental and clinical studies of ceftizoxime rectal suppositories in the field of pediatrics].

This paper deals with fundamental and clinical results, in the field of pediatrics, of the newly developed rectal suppository (CZX-S) of a cephem antibiotic ceftizoxime (CZX). CZX-S was well absorbed in children. The mean peak serum concentrations of CZX in the 125 mg-administered group (average: 9.9 mg/kg) and the 250 mg-administered group (average: 13.4 mg/kg) were 5.10-7.71 micrograms/ml at 15-30 minutes after dosing. Serum concentrations of CZX were measurable level in almost all the children at 6 hours after administration with the half-lives were 1.34-1.55 hours. The 6-hour urinary excretion rate accounted for 16.5-22.0%. CZX-S was administered to 30 children with acute upper or lower respiratory tract infections about 20-60 mg/kg/day in 3-4 divided portions. CZX-S provided favorable therapeutic-effect in most of the children 3-5 days after administration. The effectiveness rate was 93%. The causative organisms of H. influenzae (3 cases) and S. aureus (4 cases) isolated clinically from pharyngeal mucous and sputum were eradicated after administration of CZX-S. Anal pain and diarrhea experienced in 5 of the 30 children and CZX-S was withdrawn in 4 (of the 5) children, but exhibited satisfactory therapeutic-effect in 2 of the 4 cases up to withdrawal of the drug. An increase in GOT and GPT was observed in 3 cases. The values returned to the normal range in 1 case after the treatment with CZX-S. The test was not reexamined in the other 2 cases. The present clinical result suggests the usefulness of CZX-S substituted for oral and injectable forms in the treatment of various pediatric infections caused by organisms sensitive to CZX.

[Clinical studies on SM-4300, a new human gammaglobulin preparation for intravenous use in pediatrics].

Six cases of severe infections in pediatrics, which showed no or insufficient responses to treatment with antibiotics, were treated with additional intravenous infusion of SM-4300. Results were as follows. Three cases of bacterial infections with high fever, showing no response to chemotherapy, were treated with SM-4300, (68-135 mg/kg). Administration of SM-4300 resulted in defervescence, decreasing pain and swelling and showing a trend for improvement in CRP values. Administrations of SM-4300 (61-100 mg/kg) against pleurisy caused by Mycoplasma were effective in defervescence and improvement in chest findings. Clinical effects of SM-4300 were excellent in 2 cases, good in 3 and fair in 1. In this study, no clinical side reactions nor abnormal laboratory values in blood, liver or renal functions were observed.

Intramedullary spinal cord germinoma producing HCG and precocious puberty in a boy.

Extremely high concentrations of human chorionic gonadotropin in the cerebrospinal fluid were found in a 5-year-old boy presenting sexual precocity and leg pain. An intramedullary spinal cord tumor was revealed by myelogram and metrizamide computerized tomography, and a biopsy specimen taken at laminectomy. Histologically, the tumor showed germinoma with syncytiotrophoblastic giant cells. The tumor remitted for 5 months after irradiation of 3500 rad and chemotherapy, but recurred in spite of adding 7500 rad and more aggressive chemotherapy. No relapse has been seen for 1 year after amputation of the spinal cord at the T7 level.

[Study on a new cephamycin preparation cefminox in the field of pediatrics].

Cefminox (CMNX, MT-141) was studied both fundamentally and clinically in the field of pediatrics with following results. The MIC of CMNX for Bordetella pertussis was 0.10 micrograms/ml in inoculum size 10(6) cells/ml. Following administration of 10 and 20 mg/kg of CMNX as drip infusion over 1 hour, the blood levels of the drug were 49.0 +/- 18.1 and 69.1 micrograms/ml at completion of infusion, 28.8 +/- 7.7 and 61.6 micrograms/ml at 1.5 hours, 23.6 +/- 9.3 and 44.1 +/- 3.8 micrograms/ml at 2 hours and 1.4 +/- 1.4 and 4.0 +/- 0.6 micrograms/ml at 7 hours, with T1/2 of 1.03 and 1.41 +/- 0.03 hours, respectively. Within the first 7 hours after administration, 61.4 +/- 8.2 and 55.9 +/- 0.8% of the drug dosed were excreted at active form in urine. In child with encephalitis, drug considered to be good as a cephem antibiotic was achieved in the cerebrospinal fluid (the ratio of the level in the cerebrospinal fluid to that in the serum was 7.3%). In addition, in the pus in empyema also high level was reached (its ratio against blood level was 53%). In the treatment of 31 cases of acute infections of pediatric field including upper and lower airway infections, empyema, whooping cough, acute urinary tract infections and phlegmon, CMNX was administered intravenously either as one shot injection as drip infusion. The clinical results obtained were rated as good or more in 93% of the cases and as fair or more in 100% of the cases. The main dosage of CMNX in these cases was about 60 to 70 mg/kg per day in 2 or 3 divided doses. S. aureus, S. pyogenes, S. pneumoniae, H. influenzae and ABPC resistant strain of E. coli demonstrated in various materials could be eradicated after intravenous injection of CMNX. CMNX was administrated for a period of 2 to 16 days to a total amount of 1.5 to 26.5 g. In none of these cases side effects developed nor any abnormality was revealed by hematological findings or results of renal or liver function.

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

Fundamental and clinical studies have been performed on the BRL 25000 granules (combination of amoxicillin (AMPC) and potassium clavulanate (CVA) in 2: 1 ratio) in the pediatric field. In bacteriological studies a potentiated antibacterial activity of BRL 25000 was recognized against AMPC-resistant and beta-lactamase producing clinical isolates. The pharmacokinetics of the BRL 25000 granules were studied at dose levels from 10 to 20 mg/kg. The peak serum concentrations of AMPC and CVA achieved approximately 1 hour after dosing were 4.29-9.55 micrograms/ml and 3.87-4.78 micrograms/ml, respectively. The serum half-life was found to be 0.90-1.31 hours for AMPC and 1.01-1.22 hours for CVA. Six-hour urinary excretion rates were 29.5-62.6% for AMPC and 12.6-37.9% for CVA. In the clinical studies, the BRL 25000 granules were administered to 36 pediatric patients (15 with upper and lower respiratory tract infections, 10 with urinary tract infections and 11 with skin or soft tissue infections, etc.) at dose levels of 30-50 mg/kg/day. Clinical results in all cases were excellent or good. In particular, good bacterial and clinical effects were obtained against infections caused by beta-lactamase producing AMPC-resistant strains except E. cloacae 1 strain. No adverse reactions or abnormal laboratory findings were recognized in any patient.