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Hypoxic-ischemic encephalopathy is one of the main causes of neurological disabilities. It has been reported that the infarcted area can be reduced by injection of glial cell line-derived neurotrophic factor (GDNF) into the brain parenchyma after a hypoxic/ischemic insult in neonatal rats. We have shown that GDNF is expressed in neuronal and non-neuronal cells throughout all regions of the developing rat brain. We developed a system for the delivery of a constant supply of glial cell line-derived neurotrophic factor to the brain via implantation of GDNF secreting cells directly into the brain parenchyma. The aim of this study was to examine the neuroprotective effect of GDNF using this delivery system. We implanted a capsule containing GDNF secreting cells in 7 day old Wistar rats, and two days later, they underwent hypoxic-ischemic stress. The capsule provided strong neurological protection, as indicated by a reduction in the infarcted area and the severity of histological damage in the treated group compared with controls. We then investigated whether this new delivery method improved the long time learning and memory disability caused by hypoxic-ischemic stress. We examined the effect of implantation of the cells on three tasks:1) eight arm radial maze task for short memory; 2) choice reaction time task for reference memory; and 3) water maze task for long term memory. In all of the three tasks, implantation of the GDNF capsule improved learning and memory disability. Glial cell line-derived neurotrophic factor treatment is effective not only in reducing brain damage but also in preventing learning and memory impairment following hypoxic-ischemic insult in neonatal rats.

Once a day of arbekacin (ABK) administrations based on a new object of peak concentration setting on 9-20 microg/mL were performed to 14 neonates. The gestational ages were 27.3 +/- 4.2 weeks. As to the preparing initial dosage, Therapeutic Drug Monitoring Program soft was used. Mean daily dose of 6.2 +/- 0.4 mg/kg bodyweight was administered every 24 to 48 h by 30 min intravenous infusion. Mean serum peak concentrations of ABK and those of trough concentrations were 15.2 +/- 4.3 microg/mL and 2.0 +/- 1.4 microg/mL respectively. The relationship between the measured values (y) and predicted values (x) showed the regression equation y = 0.969 + 0.931x (R2 = 0.769, n = 35), which suggested the usefulness of the dosage design. Overall clinical effectiveness was 78.9% (11/14). There were no obvious adverse effects including abnormal auto auditory brainstem responses and serum creatinine increase. Effectiveness rate and no adverse effects suggested that once a day of ABK therapy in neonate including extremely preterm infant was preferable regimen.

The therapeutic use of vitamin D in the OB-GYN field is well known for osteoporosis in the climacteric stage, and vitamin K is for the protection of neonatal hemorrhage. The therapeutic use of vitamin E was reviewed, and it was concluded that there was a large number of diseases for example, sterility, toxemia of pregnancy, IUGR, neonatal jaundice, climacteric syndrome, in which a therapeutic value for vitamin E could be clearly establish, vitamin K prophylaxis is also under taken for the neonate. This can be done by giving a dose to the mother just before or in the early stages of labor. Ubiquinone, was given to the man for the treatment of oligospermia. CoQ10 also warrants further investigation for the treatment of fetal arrhythmia in utero.

A patient with benign familial neonatal convulsions was presented. The patient had the first episode of cyanosis on the second day of life. Thereafter, he also experienced focal clonic and/or multifocal clonic seizures. The interictal EEG showed no definite abnormality. Between the seizures he appeared well and physical examination was essentially normal. Treatment with phenobarbital (4 mg/kg/day, P. O.) was started and subsequently he had no further seizures until 3 months. At the age of 4 months, he was admitted to the hospital again because of generalized tonic-clonic seizures. The interictal EEG showed sporadic spikes dominantly in the right central area. The findings of ictal EEG at that time are characterized by fast spiking of increasing amplitude during the tonic phase. During the clonic phase, there are repetitive+ bursts of spikes and sharps mixed with persisting muscle potential. The termination of the convulsion is characterized by general voltage depression. Clinical characteristics such as seizure types, EEG findings, responses to antiepileptic drugs and recurrence of the seizures found in our propositus were compared with those of the patients previously reported in the literature.

Studies were carried out on the in vivo kinetics and clinical efficacy of latamoxef (LMOX) in neonates and premature infants. The results are summarized below. Serum concentration and T1/2 following intravenous injection of LMOX to neonates LMOX was intravenously administered to neonates as one shot doses of 10 mg/kg and 20 mg/kg. The serum concentration of LMOX showed a dose-response to the 10 and 20 mg/kg doses in each of the 0--3 day-old group, 4--7 day-old group and 8--28 day-old group. The T 1/2 values were as follows; for the 10 mg/kg dose, 5.17 hours in the 0--3 day-old group, 3.28 hours in the 4--7 day-old group and 2.79 hours in the 8--28 day-old group; for the 20 mg/kg dose, 5.58 hours in the 0--3 day-old group, 3.46 hours in the 4--7 day-old group and 3.14 hours in the 8--28 day-old group. Thus, it is seen that the half-life of both dosages decreased as the infants became older. Serum concentration and T 1/2 following intravenous injection of LMOX to premature infants Similar to the case of neonates described above, the concentration of LMOX in the serum of the premature infants showed a dose-response to the 10 mg/kg and 20 mg/kg dosages. The T 1/2 values for the 0--3, 4--7 day-old and 8--28 day-old groups were 7.54, 3.93 hours and 6.25 hours, respectively, for the 10 mg/kg dose, and 10.8, 4.05 hours and 3.23 hours, respectively, for the 20 mg/kg dose. Again, it is seen that the half-life of both dosages decreased as the age of the prematurely-born infants increased. Serum concentration and T1/2 following 1-hour intravenous drip infusion of LMOX to neonates LMOX was administered to neonates in doses of 10 mg/kg and 20 mg/kg, by i.v. drip infusion over a 1-hour period. With both dosages, the peak serum concentration of LMOX occurred at the time of completion of the infusion. The T1/2 values for the 0--3, 4--7 day-old and 8--28 day-old groups were 5.41, 3.68 hours and 1.92 hours, respectively, for the 10 mg/kg dose, and 5.31, 2.67 hours and 4.86 hours, respectively, for the 20 mg/kg dose. Urinary excretion of LMOX in neonates and premature infants. The percentage of the administered LMOX dose contained in the urine excreted during the 6-hour period following intravenous administration of LMOX to neonates and premature infants was determined.(ABSTRACT TRUNCATED AT 400 WORDS)

Fundamental and clinical investigations of cefotaxime were carried out in neonates. The following results were obtained. 1. Seven neonates with serious infections caused by identifiable pathogens, including Group B streptococcal meningitis and Group A streptococcal sepsis, were treated by intravenous bolus injection of 20-200 mg/kg of cefotaxime 2 or 3 times daily (60-400 mg/kg/day). The clinical efficacy of cefotaxime was assessed to be good in 6 patients and fair in 1 patient. Bacteriological efficacy was evaluable in 4 patients, all of whom displayed complete eradication of pathogens. 2. Among 22 neonates administered cefotaxime, adverse reactions appeared in 3 patients. Adverse reactions consisted of a transient skin rash in 1 patient and elevation of GOT in 2 patients. 3. Serum concentrations of cefotaxime and desacetyl cefotaxime were investigated in 8 mature infants and 5 immature infants on days 0-7 postpartum. A single intravenous injection of 20 mg/kg produced peak serum concentrations of 31.8-49.7 mcg/ml, associated with a half-life of 1.38-4.47 hours, in mature infants and peak serum concentrations of 35.5-55.0 mcg/ml, associated with a half-life of 3.22-6.43 hours, in immature infants. On days 0-2 postpartum the half-life was longer than on subsequent days. This tendency was particularly remarkable in immature infants. Serum concentrations of desacetyl cefotaxime displayed high individual variations; no consistent trends were noted. 4. Cefotaxime and desacetyl cefotaxime serum concentrations were studied in 3 neonates undergoing exchanged transfusion (exchanged volume 177-180 ml/kg) on 1-4 days postpartum. Serum concentrations of cefotaxime after exchanged transfusion were equivalent to 32.6-63.9% of the pretransfusion level, while those of desacetyl cefotaxime were 75.2-106% of the pretransfusion level. 5. Minimal inhibitory concentration (MICs) and minimal bactericidal concentration (MBCs) of cefotaxime were determined against clinical isolates. MICs for inoculum sizes of 10(8)/ml and 10(6)/ml were respectively 3.13-25 mcg/ml and 3.13-25 mcg/ml against S. aureus, 0.024 mcg/ml and 0.012 mcg/ml against Group A Streptococcus, 0.05 mcg/ml and 0.05 mcg/ml against Group B Streptococcus and 0.39 mcg/ml and 0.1 mcg/ml against E. coli. MBCs for an inoculum size of 10(6)/ml were 3.13-100 mcg/ml or over against S. aureus, 0.012 mcg/ml against Group A Streptococcus, 0.39 mcg/ml against Group B Streptococcus and 1.56 mcg/ml against E. coli.

It has been proven that, when cephem group antibiotics are administered intravenously to neonates, the peak serum level of the drug is higher, and the half-life is longer, compared with the values attained in suckling infants. The same pattern is seen even with cefmetazole. This is, the Post- and Perinatal Period Research Group recently reported that, when 20 mg/kg of cefmetazole was administered intravenously, the mean serum half-life of the drug was 4.18 hours in infants up to 3 days after birth, while by about the age of 2 weeks there was no longer a difference with suckling infants. In the present study, cefotaxime was administered at a dosage level of 20 mg/kg by intravenous drip infusion over a 30-minute period. The administered subjects were a 16-day-old neonate and a 45-day-old suckling infant, and the serum level of cefotaxime was monitored. The peak concentration was found to be higher in the younger subject, and the half-life in the serum was longer, i.e., 2.52 hours compared with 1.5 hours in the suckling infant. In addition, 4 cases of newborn infection were treated with cefotaxime at 120--504 mg/day (approximately 35--300 mg/kg/day), given intravenously for a period of 6 to 21 days. Clear clinical efficacy and bacteriological efficacy were achieved in relation to 1 case of staphylococcal pneumonia, 1 case of septicemia compounded by purulent meningitis caused by Enterobacter aerogenes and 1 case of fever of undetermined origin. The following summarizes the results of the present study. 1) There was no adverse effect exerted on the hepatic or renal functions. 2) Cefotaxime was efficacious in the treatment of neonates suffering from infections caused by staphylococci and a Gram-negative rod.

The authors studied the antibacterial activity, absorption and excretion, and clinical use of cefmetazole in neonatal period, and obtained the following results. 1. The minimal inhibitory concentrations (MICs) of cefmetazole (CMZ) were measured, to compare with those of cefazolin (CEZ), for clinical isolates of S. aureus (31 strains), E. coli (29 strains) and K. pneumoniae (30 strains). On a cumulative percentage basis, 77% of S. aureus, 76% of E. coli and 90% of K. pneumoniae were inhibited by less than or equal to 3.13 microgram/ml of CMZ with a higher inoculum size. When compared with CEZ, MICs of CMZ were found to be superior or equal against E. coli, K. pneumoniae and some of S. aureus, but to be inferior against most of S. aureus. Most of strains which were resistant to CEZ were most sensitive to CMZ. These results suggest that CMZ is highly active against Gram-negative bacteria and is stable to beta-lactamase. 2. The serum concentration was measured in 7 neonates (5 approximately equal to 25 day-old) and 5 infants (1 approximately 3 month-old) after a single intravenous administration of 20 approximately 25 mg/kg of CMZ. The mean concentration in neonates was 68.3 microgram/ml at 1/2 hour postinjection, 57.0 microgram/ml at 1 hour, 35.4 microgram/ml at 2 hours, 18.1 microgram/ml at 2 hours, 18.1 microgram/ml at 4 hours and 9.5 microgram/ml at 6 hours. The mean half-life was 2.04 hours. The peak concentration of each neonate seemed to be related more to individual variation than to the days after birth. The mean concentration in infants was 60.7 microgram/ml at 1/2 hour, 42.8 microgram/ml at 1 hour, 22.2 microgram ml at 2 hours, 9.2 microgram/ml at 4 hours and 3.2 microgram/ml at 6 hours. The mean half-life was 1.31 hours. There was little difference in the mean peak concentration between neonates and infants, but the mean concentration after that were higher in neonates than infants. It was apparent that the half-life tends to be shortened in proportion to advanced age in days and months. 3. CMZ was administered clinically in 3 cases of acute bronchopneumonia. Its clinical effect was excellent or good in all of the cases. No adverse reaction or abnormal laboratory values were found.

1. Medium to large amount of CMZ (100-270 mg/kg/day) was administered to 4 cases of neonatal infants having severe infections due to pathogenic E. coli and sepsis due to E. coli CMZ was remarkably effective in all cases, and the causative bacteria disappeared in 100%. 2. Among 10 cases which administered CMZ, 5 cases showed side effect. Eruption, diarrhea and increase of GOT, GPT and LDH activities were observed but no case suggested interruption of administration. 3. Blood level of CMZ was determined in 4 cases of 0-1 day old, premature infants. The half life of CMZ was 8.55-15.3 hours, prolonged considerably, and 12 hours after one shot (20 mg/kg) of intravenous CMZ administration, 20.2 microgram/ml of blood level was maintained. 4. Intraspinal CMZ level was determined in aseptic meningitis. When one shot 50 mg/kg CMZ was given intravenously, intraspinal CMZ levels after 30 minutes and 1 hour were 20.3 microgram/ml and 34.5 microgram/ml, respectively, and distribution of CMZ in the cerebrospinal fluid was shown to be excellent. 5. Exchange blood infusion (amount of exchange, 170 ml/Kg) was performed in a small premature newborn baby, and blood transformation of CMZ was examined. It was found as the result that the blood level of CMZ was decreased to 53% of the pretreated level. 6. MIC of CMZ was examined in 3 strains of E. coli isolated from blood and cerebrospinal fluid. MICs were 0.39-0.78 microgram/ml when 10(6)/ml was inoculated and 0.78-1.56 when 10(8)/ml was inoculated.

Cefminox (CMNX, MT-141) was evaluated for its safety and efficacy in children. Fifteen cases of bacterial infections were treated with intravenous bolus injections of 30 to 100 mg/kg/day of CMNX. Each 5 cases of acute respiratory tract, urinary tract, and gastrointestinal infections were included. All the cases were cured after the CMNX therapy. No adverse reactions were encountered with the therapy. The serum half-life was approximately 1.5 to 2 hours after intravenous bolus injection in children. The data suggest that CMNX is a safe and effective antibiotic when used in children with susceptible bacterial infections.

Purulent meningitis in patients admitted to the pediatric department of Kyoto University Hospital and affiliated institutions from 1951 through 1973 were studied with emphasis on the kinds of the causative organisms and the susceptibility of these organisms to antibiotics. The findings in this study have served to help select antibiotics most likely to be effective against this disease. The overall incidence of purulent meningitis was 0.68%. This figure decreased little throughout the period. As for the frequency of causative organisms, Neisseria meningitidis led the list, and Diplococcus pneumoniae ranked just behind. Haemophilus influenzae was rare. The frequency of N. meningitidis, however, decreased sharply in spite of the essentially unchanged overall incidence of this disease. The probable reason for the poor prognosis of this disease in spite of the remarkable strides in chemotherapy is the decreased frequency of N. meningitidis and the inversely increased organisms that are resistant to usual chemotherapy. The therapeutic effectiveness of cefazolin against this disease was studied in 15 children including eight newborns and four infants. The daily per kg bodyweight dose was 50 mg or less in four, 50 approximately 100 mg in five, and more than 100 mg in the remaining six. The route of administration was either intramuscular or intravenous. No deaths occurred. The rate of effectiveness was as high as 80%. Residual symptoms were recorded in six and, in as many as five of them, the cause was a-tributable to the delayed detection of the disease. Neither side effects nor aberrent laboratory findings attributable to large doses of cefazolin were recorded. Diffusibility of cefazolin into the CSF was studied in nine subjects. The CSF concentration of this antibiotic was shown to be somewhat lower than that of ampicillin or cephaloridine and to account on an average for 13% of the mean peak serum level. This relatively low diffusibility will be offset by its high serum concentration and safe large-dose therapy. These findings have clearly shown that the therapeutic effectiveness of cefazolin is as high as that of ampicillin, and that this excellent effectiveness holds true even when the causative organism happens to be Escherichia coli, Klebsiella, etc. that are resistant to ampicillin. The authors have furthermore scrutinized much literature on the frequency of the causative organisms, emergence of resistant strains, and the diffusibility of antibiotics into the CSF, and arrived at the conclusion that cefazolin is a promising antibiotic of choice for the treatment of purulent meningitis in newborn. The daily dose is preferably 150 mg/kg or more given in three divided intravenous doses. Meanwhile ampicillin proved to be useful as the antibiotic of choice for the treatment of purulent meningitis in infants and children.

Cefotaxime (CTX) was used in the treatment and prophylaxis of infections in neonates and immature infants. The following results were obtained. 1. Mean serum concentrations (bioassay) 30 minutes after a single intravenous injection of about 20 mg/kg of CTX were 44.5 mcg/ml in neonates and 47.2 mcg/ml in immature infants aged 0-3 days, 45.8 mcg/ml in neonates and 56.4 mcg/ml in an immature infant aged 4-7 days and 40.6 mcg/ml in neonates and 38.1 mcg/ml in immature infants aged 8 or more days. Six hour values were respectively 10.9 mcg/ml, 17.0 mcg/ml, 4.6 mcg/ml, 13.4 mcg/ml, 3.8 mcg/ml and 2.7 mcg/ml. 2. Mean serum concentration half-lives were 3.0 hours in neonates and 3.2 hours in immature infants aged 0-3 days, 1.8 hours in neonates and 3.2 hours in an immature infant aged 4-7 days, and 1.5 hours in neonates and 1.6 hours in immature infants aged 8 or more days. 3. Urinary recovery rates were 0.8-78.0% for 0-6 hours after treatment. 4. Adequate clinical efficacy can be expected by the intravenous injection of CTX in doses of 20 mg/kg 2 times daily, every 12 hours, in neonates and immature infants aged 0-3 days, 20 mg/kg 3 times daily, every 8 hours, in neonates and immature infants aged 4-7 days, and 20 mg/kg 3 to 4 times daily, every 6-8 hours, in neonates and immature infants aged 8 or more days. 5. The clinical efficacy of CTX was good in all 4 cases of sepsis (including suspected case), excellent in 1 case of urinary tract infection, and good in all 4 cases of fever of unknown origin for a cure rate of 100%. 6. Adverse reactions were not noted in any cases.

CMZ is a derivative of cephamycin antibiotics having a potent resistance to beta-lactamase, so that it exerts strong effect on beta-lactamase producing resistant strain, and it is an antibiotic agent having wide antibacterial spectra. Highly effective and safe properties were proved and identified in children (Presented at 11th I.C.C.), so that a study group was organized to examine the usefulness of CMZ for the various infections of the newborn and immature infants. Blood level and urinary excretion: A half life (T 1/2) of the intravenously administered CMZ (20 mg/kg) in blood was 4.18, 2.39 and 1.78 hours in less than or equal to 3 days, 4 to 7 days and greater than or equal to 8 days old newborn infants, respectively. Immature infants reveals longer T 1/2 by 3 days after birth but normalizes fairly soon. Urinary excretion of CMZ was examined in 10 infants up to 7 days old. The relation between the urinary volume and urinary recovery were well correlated. Clinical effect: CMZ was administered to respiratory infections, septicemia, meningitis, urinary tract infections, and other infections in 51 cases of newborn and immature infants. A daily dose, 60 to 100 mg/kg, was divided in 2 to 4 times, and administered intravenously. The causative organisms were E. coli, Klebsiella, Serratia and Staph, aureus and 97% of eradication rate was obtained. CMZ was clinically effective in 100% for respiratory infections (17 cases), septicemia (7 cases) and purulent meningitis (4 cases), and in 91.7% for UTI. The overall effective rate was 94.1%. No notable adverse effect was found. Cefmetazole is a safe and effective antibiotics in treating severe infections in newborn and immature infants.

Cefamandole (CMD) was intravenously drip infusion administered at daily dose of 400 mg/kg to the neonate with purulent meningitis caused by E. coli which was resistant to ABPC. In clinical application, CMD was evaluated as effective, although 6 mg/kg/day of GM given concomitantly. No adverse effect and abnormal laboratory findings were observed. This study would support the clinical usefulness of CMD in severe neonatal infection especially like meningitis.

One full-term newborn infant and 2 premature ones were treated with cefotaxime for the treatment of suspected sepsis and umbilical suppurative inflammation. Pathogenic organisms could not be identified in all cases. A good result was obtained with the case of suspected sepsis. But the other 2 cases were not evaluable because underlying diseases such as massive pulmonary atelectasis or respiratory distress syndrome masked the effects of this agent. Serum levels of cefotaxime in 3 of the 4 cases were determined with bioassay. Time courses of the serum levels in 2 of them resulted in peculiar biphasic disappearance curves. This fact implies the possibility that desacetylation of cefroxime proceeds also in newborns as in adults and that desacetyl metabolite accumulates in the body owing to the premature function of the neonatal kidney.

Clinical evaluation of cefmetazole were made in the treatment of bacterial infections in the newborn infants and the following results were obtained. 1) Five infants, 7 approximately 58 days of age, received a single intravenous one-shot injection of 22.2 approximately 24.5 mg/kg dose of cefmetazole, and blood concentrations were determined. The average level was 62.6 micrograms/ml (30 minutes), 46.3 micrograms/ml (1 hour), 26.8 micrograms/ml (2 hours), 8.7 micrograms/ml (4 hours) and 2.4 micrograms/ml (6 hours), and T 1/2 was 87.7 minutes. Almost similar values were obtained when the drug was given by a 30-minute drip infusion and sufficiently exceeded the MIC to the bacteria to which cefmetazole was indicated. 2) In two patients, who had been operated for choledochal cyst and received an intravenous drip infusion of the drug, the persistence of the blood concentration was remarkably long, T 1/2 being 192 and 222 minutes, respectively. This problem still remains to be elucidated. 3) The following 22 patients were treated with an intravenous one-shot or drip infusion of cefmetazole, i.e., 45.6 to 107.1 mg/kg divided in 2 approximately 3 doses; 14 patients aged 1 to 21 days, 2 aged 1 to less than 2 months, 3 aged 2 to less than 3 months and 3 aged older than 3 months. However, in purulent meningitis, larger dose was given intravenously 6 times daily. Diseases included sepsis (4 cases), purulent meningitis (3), peritonitis (1) SSS syndrome (3), subcutaneous abscess (2), urinary tract infection (8) and Salmonella enteritis (1), and their causative organisms were E. coli (13 strains), K. pneumoniae (1), S. typhimurium (1), S. aureus (6) and group B Streptococcus (1). Overall efficacy rate in 22 cases was 90.9%. i.e., excellent in 11, good in 9 and failure in 2. Two cases of failure were a patient with peritonitis and visceral eventration due to umbilical hernia and a patient with a chromosomal aberration and urinary tract infection caused by E. coli. Reasons for such a treatment failure appeared to reside in host factors. 4) Adverse reactions included each one case of skin rash and diaper rash, 3 cases of eosinophilia and 5 cases of elevation of transaminase levels, all of which were mild and transient. 5) Based on the above results, cefmetazole is considered to be a potent new antibiotic which should be indicated as the first choice drug in the treatment of neonatal bacterial infections. The recommended dosage is as follows: 50 mg/kg given intravenously 6 times daily for bacterial meningitis and 20 approximately 25 mg/kg intravenously or by a drip infusion 2 to 3 times daily for other infections.