Placental transfer of IgG subclasses in a Japanese population.

BACKGROUND: Maternal immunoglobulin G (IgG), transferred across the placenta to the fetus during intrauterine life, is an important component of the neonatal immunological defence mechanisms against infection. There is controversy with respect to differences in placental transfer of the different IgG subclasses, and no definite data are available on a Japanese population. Therefore, we investigated placental transfer of IgG subclasses in a Japanese population. METHODS: A total of 228 matched pairs of cord and maternal serum samples (20-42 weeks gestation) were assayed for each IgG subclass by an enzyme-linked immunosorbent assay. RESULTS: The mean values and hierarchy of cord/maternal concentration ratios of IgG subclasses at 40 weeks gestation were as follows: IgG1(1.47) > IgG3(1.17) = IgG4(1.15) > IgG2(0.80). The cord/maternal concentration ratios of all IgG subclasses were positively correlated to gestational age. The mean ratios for IgG1 and IgG4 nearly reached a plateau at 39 and 37 weeks gestation, respectively, while those for IgG2 and IgG3 increased until 41 weeks gestation. The ratios of all IgG subclasses for full-term deliveries were reciprocally correlated to the respective maternal IgG subclass serum levels. CONCLUSIONS: The results suggest that although all four IgG subclasses are actively transferred across the placenta, the efficiency of their transfer ranks in the order IgG1 > IgG3 = IgG4 > IgG2. The different results as to placental transfer of IgG subclasses in the literature might be due, at least in part, to different maternal IgG subclass serum levels in the populations studied.

[Cousins with X-linked recessive myotubular myopathy].

We describe two cousins with severe infantile form of myotubular myopathy. In Japan this disease has previously been reported in only three families. Case 1. The propositus, a 2-year-5-month-old boy, had been on a respirator since birth. He had a history of severe neonatal asphyxia and sequential hypotonia with dyspnea. Findings diagnostic of congenital myotubular myopathy, such as central nuclei and peripheral halo of muscle fibers, were demonstrated in his biopsied muscle. Case 2. A male the cousin of case 1 had congenital myopathy and died at 3 months of age due to respiratory failure. His muscle biopsy disclosed the identical findings as had been seen in case 1. These two cases were born to twin mothers, suggesting X-linked recessive inheritance. Early diagnosis and proper treatment of myotubular myopathy are important, because this condition may be erroneously-interpreted as the sequelae of neonatal asphyxia.

Interstitial deletion of chromosome 1q [del(1)(q24q25.3)] identified by fluorescence in situ hybridization and gene dosage analysis of apolipoprotein A-II, coagulation factor V, and antithrombin III.

We report on a 12-month-old Japanese boy with an interstitial deletion of the long-arm of chromosome 1 and meningomyelocele, hydrocephalus, anal atresia, atrial septal defect, left renal agenesis, bilateral cryptorchidism, talipes equinovarus, low birth weight, growth/developmental retardation, and many minor anomalies. By conventional GTG-banding, his karyotype was first interpreted as 46,XY,del(1)(q23q24), but it was corrected as 46,XY.ish del(1)(q24q25.3) by fluorescence in situ hybridization using 11 known cosmid clones as probes. His serum levels of apolipoprotein A-II (gene symbol: APOA2, previously assigned to 1q21-q23) and coagulation factor V (F5, 1q21-q25) were normal, while serum concentration and activity of antithrombin III (AT3, 1q23-q25.1) was low. The results indicated that localization of APOA2 and F5 are proximal to the deleted region and AT3 is located within the deletion extent in the patient.

[Pharmacokinetic, bacteriological and clinical studies on cefozopran in neonates].

Cefozopran (CZOP) was administered to nine newborn patients with infections at a dose of 20 mg/kg twice or three times daily for 5 to 6 days to evaluate the efficacy, safety and pharmacokinetics of cefozopran. 1. Blood concentrations CZOP was intravenously given to 6 newborn patients by drip infusion at a dose of 20 mg/kg over 30 minutes. The maximum blood concentrations (Cmax) were 38.4 micrograms/ml in a patient aged 0 day, 37.7 and 54.3 micrograms/ml in two patients aged 1 day, 51.3 and 64.1 micrograms/ml in two patients aged 3 days and 51.0 micrograms/ml in a patient aged 5 days. Cmax was lower in the patient aged 0 day. The elimination half life (T 1/2) was 9.2 hours in the patient aged 0 day, 4.9 and 3.7 hours in the patients aged 1 day, 3.1 and 2.4 hours in the patients aged 3 days and 2.9 in the patient aged 5 days, showing a prolongation of T 1/2 in patients of lower age. 2. Urinary excretion Of the 6 patients given CZOP at a dose of 20 mg/kg by intravenous drip infusion over 30 minutes, urine was collected in 5 patients. The cumulative excretion rate within 6 hours after infusion was as low as 19.8% of dose in the patient aged 0 day. The rates were elevated as high as 46.3 and 57.0% of dose in the patients aged 1 day. In the patient aged 3 days, the recovery within 4 hours after infusion was 47.3%. It was 70.6% of dose within 6 hours after dosing in the patient aged 5 days. The urinary recovery within 6 hours after dosing increased with the advance of age. 3. Clinical results Efficacy was evaluable in 7 patients. Of them, 3 had suspected septicemia, 2 pneumonia, 1 intrauterine infection and 1 urinary tract infection. The clinical efficacy was judged "excellent" in all the evaluable patients. Neither adverse drug reactions of signs and symptoms nor abnormal alterations of the laboratory test values were recognized in the 9 patients evaluable for safety. These results suggest that CZOP is an effective and safe drug for treatment of infections in the newborns. As for the dosage and method of administration from the view of the pharmacokinetic data obtained, intravenous drip infusion of 20 mg/kg once or twice daily was considered to be sufficient for patients aged 0 day. For patients aged 1 to 7 days and those aged 8 days or elder, the administration of twice to 3 times daily and 3 to 4 times daily were considered to be sufficient, respectively.

[Pharmacokinetic, bacteriological and clinical studies on cefozopran in neonates and premature infants. A study of cefozopran in the perinatal co-research group].

The following results were obtained in pharmacokinetic, bacteriological and clinical investigations of a cephem antibiotic for injection, cefozopran (SCE-2787, CZOP), administered to neonates and premature infants. 1. Pharmacokinetics (1) Half-lives (T 1/2's) of CZOP in 0-day-old (less than 24 hours after birth) neonates and premature infants were longer than those in 1-day-old or older infants. When half-lives were compared between 0-day-old neonates and 0-day-old premature infants, longer half-lives were observed in premature infants. (2) When CZOP was intravenously administered to 1-day-old or older neonates and premature infants at a dose of 20 mg/kg, no differences were noted in blood concentrations between neonates and premature infants from 30 minutes to 6 hours after administration as well as T 1/2's. (3) Blood concentration of CZOP administered at doses of 10, 20 and 40 mg/kg were dose-dependent. (4) Urine excretion rates of CZOP administered to 1-day-old or older neonates and premature infants were approximately 30 to 60% in the first 6 hours after administration. Urine excretion rates in 0-day-old neonates and premature infants were low. 2. Clinical results (1) Of a total of 136 cases to which CZOP was administered, clinical efficacy evaluation was possible in 96 cases, and safety evaluation in 132 cases. (2) The clinical efficacy rates were 78.6% (22/28) in 28 cases in which causative organisms were detected (Group A), and 97.1% (66/68) in 68 cases in which no such organisms were detected (Group B), with the total efficacy rate (Groups A and B) of as high as 91.7% (88/96). (3) Bacteriological evaluations were made with 33 strains isolated from the 28 cases of Group A. Elimination rates for Gram-positive and Gram-negative bacteria were 88.2% (15/17) and 92.3% (12/13), respectively, with the total elimination rate of 90.0% (27/30). No microbial substitution was noted. (4) As an adverse reaction, diarrhea was noted in one case (0.8%). Abnormal laboratory test values were noted in 15 cases (12.3%) including eosinophilia, elevated GPT, and elevated gamma-GTP. All of these abnormalities were transitory, and none of them critical. As a result of above pharmacokinetic and clinical investigations, CZOP is considered to be highly useful in the treatment of indicated infections in neonates and premature infants. It appears that 20 mg/kg of CZOP can be administered by intravenous injection or intravenous drip infusion to neonates and premature infants aged 0-day (less than 24 hours after birth) once or twice daily, to those aged 1 (24 or more hours after birth) to 7 days twice or three times daily, and to those aged 8 or more days three to four times daily, and that the dose can be increased up to 40 mg/kg in cases of critical or intractable infections.

[A case of congenital brain tumor diagnosed during follow-up of neonatal intracranial hemorrhage].

We describe a three-year-old girl whose growing congenital brain tumor may have been responsible for her perinatal intracranial hemorrhage. The patient, born after an uneventful pregnancy and delivery, had an intracranial hemorrhage in the right frontal area, including the basal ganglia, as a newborn. Her only symptoms at that time were vomiting and fever. She improved both, clinically and neuroradiologically during the following weeks, and except for mild left hemiparesis, the patient developed with no other apparent neurological deficits. However, a follow-up brain CT scan at 3 years of age, disclosed a heterogeneous tumor with a 5 cm diameter in the same right frontal area as the neonatal hemorrhage. The tumor was surgically removed, and diagnosed as a benign mixed tumor composed of differentiated astrocytoma and meningioma elements. It is conceivable that the brain tumor may have been growing rather slowly since an early fetal stage. This case indicates the need of being aware that neonatal intracranial hemorrhages may be caused by bleeding of congenital brain tumors.

The induction of cardioangitis by Lactobacillus casei cell wall in mice. I. The cytokine production from murine macrophages by Lactobacillus casei cell wall extract.

A single intraperitoneal injection of the water-soluble cell wall extract from Lactobacillus casei (LCWE) in mice can induce acute inflammatory heart involvement such as cardiac arteritis, similar to the heart lesions in Kawasaki disease. To clarify whether inflammatory cytokines participate in pathogenic mechanisms of LCWE-induced cardioangitis in mice, we studied in vitro cytokine production (IL-1, TNF alpha, and IL-6) from peritoneal macrophages (M phi) stimulated with LCWE in comparison with that of lipopolysaccharide (LPS). LCWE significantly activated M phi of BALB/c in production of IL-1 and TNF alpha compared with LPS. However, the magnitude of IL-6 synthesis by LCWE was approximately similar to that of LPS. These results demonstrate that the pathogenesis of LCWE- induced cardiac lesions may be associated with increased production of inflammatory cytokines.

Application of typing by pulsed-field gel electrophoresis to the study of Clostridium difficile in a neonatal intensive care unit.

Pulsed-field gel electrophoresis (PFGE) analysis of restriction pattern polymorphism was applied to type Clostridium difficile isolated from neonates hospitalized in a neonatal intensive care unit, and the results were compared with those of immunoblot analysis. C. difficile was isolated from fecal specimens of 41 (61%) of 67 neonates during a 5-month investigation. All of these neonates were asymptomatic. Fifty-five C. difficile isolates from 32 patients were analyzed by PFGE after digestion with SmaI and SacII endonucleases and by immunoblotting with 10 different antisera. Fifty-three of 55 isolates from 30 patients were identical by PFGE analysis after SmaI and SacII digestion and immunoblot analysis. Two isolates were different from each other and from the epidemic group by both PFGE and immunoblot analysis. All 53 epidemic isolates were nontoxigenic, while the two remaining isolates were toxigenic. These results suggest that nosocomial spread of nontoxigenic C. difficile infection in the neonatal intensive care unit and suggest that both PFGE and immunoblot are powerful typing tools for the epidemiological study of C. difficile.

Suppressive effect of intravenous immunoglobulins on the activity of interleukin-1.

In order to study the effect of human immunoglobulin preparations for intravenous use (IVIg) on the production and activity of interleukin-1 (IL-1) derived from monocytes, we treated cultured monocytes with IVIg and examined the lymphocyte-activating factor (LAF) activity of IL-1 in the culture supernatants. The results showed that IVIg suppressed the activity from most healthy adults and some febrile children with acute respiratory disease or Kawasaki disease. Further studies revealed that intact Ig (whole molecular Ig) did not suppress the mRNA expression of IL-1 alpha or IL-1 beta in mononuclear cells, that intact Ig and pepsin-digested Ig inhibited the LAF activity of recombinant IL-1 (rIL-1) and also that intact Ig contains immunoglobulin (probably anti-IL-1 antibody) which binds with rIL-1 by dot blotting using biotin-streptavidin. These results suggest that IVIg suppresses neither IL-1 synthesis nor the release of IL-1 from monocytes but does neutralize IL-1 alpha and IL-1 beta activity by binding IL-1 proteins as an anti-IL-1 antibody.

11q trisomy detected by fluorescence in situ hybridization.

A patient with psychomotor developmental delay, multiple minor anomalies, congenital heart disease and left inguinal hernia is reported. His karyotype was 45,X/46,X,+mar (3:37 cells), and the marker chromosome was identified as t(Y;11)(q12;q14?) using fluorescence in situ hybridization and fluorescent chromosome painting. He was diagnosed as mosaic for de novo 11q trisomy.

[Clinical and pharmacokinetic studies on aztreonam in neonates].

Clinical and pharmacokinetic studies on aztreonam (AZT) were performed in neonates. The results are summarized as follows: A total of 6 cases consisting of 5 mature and 1 low-birth-weight infants was clinically evaluated. AZT 20 mg/kg was administered 2-3 times daily, via 1 hour intravenous drip infusion for 6-21 days. Concomitantly, vancomycin (VCM) 15 mg/kg was administered to 1 case 3 times daily, via 1 hour intravenous drip infusion for 3 days and ampicillin (ABPC) 20-50 mg/kg to 3 cases 3 time daily via 30 minutes intravenous drip infusion for 2-6 days. Of the 6 bacterial infection cases (1 with sepsis and purulent meningitis, 2 with sepsis, 2 with urinary tract infection and 1 with perirectal abscess), clinical effects of AZT were evaluated in 4 cases (2 each with sepsis and urinary tract infection) as "excellent" in all the cases. All of the causative organisms (Escherichia coli in 3 and Enterobacter cloacae in 1) were eradicated by the treatment with AZT. Neither clinical side effect nor abnormal laboratory test value caused by AZT was observed. MICs of AZT against 10 clinical isolates (Staphylococcus aureus 1, E. coli 4, Klebsiella pneumoniae 1, E. cloacae 1, Haemophilus influenzae 1 and Pseudomonas aeruginosa 2) from neonatal patients with bacterial infections were examined. As results, AZT showed very good antibacterial activity comparable or even superior to cefoperazone, cefotaxime, latamoxef; however, the activity against P. aeruginosa was inferior to imipenem.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacokinetics and clinical studies on aztreonam in neonates and premature infants (the first report). Study on effectiveness and safety in mono-therapy with aztreonam. A study of aztreonam in the Perinatal Co-research Group].

Pharmacokinetics and clinical study of aztreonam (AZT) in neonates and premature infants were conducted with the following results: 1. Pharmacokinetics (1) Serum concentrations of AZT at 30 minutes after one-shot intravenous injection of 10 mg/kg and 20 mg/kg to neonates including premature infants were 20.6-26.6 micrograms/ml and 38.5-46.4 micrograms/ml, respectively, and decreased thereafter. A dose response was observed in the serum concentrations with administration of AZT 10 mg/kg and 20 mg/kg. (2) Serum half-lives (T1/2) tended to be shorter in both mature and premature infants as their day-ages increased and T1/2 tended to be prolonged in premature infants compared with mature infants. (3) Changes in serum concentration upon one-hour intravenous drip infusion of AZT 20 mg/kg were very similar to those upon one-shot intravenous injection. (4) Urinary excretions in the first 6 hours after one-shot intravenous injection of AZT 10 mg/kg or 20 mg/kg tended to increase in mature infants as they grew and showed excretion rate of 26.2-54.3% but those in premature infants did not show any specific tendency with rate of 17.5-45.1%. Urinary excretions upon intravenous drip-infusion showed a tendency very similar to those upon intravenous injection. 2. Clinical studies (1) Clinically evaluable cases of AZT treatment were 88 cases (91 diseases), in which pathogenic organisms were identified in 56 cases (Group A), i.e., sepsis 9, purulent meningitis 2, pneumonia 8, urinary tract infection (UTI) 33 and others. Total efficacy rate was 98.2% including "excellent" (39), "good" (16) and "fair" (1). Number of cases in which pathogenic organisms were unknown (Group B) was 11, i.e., suspected sepsis (4), pneumonia (3) and intrauterine infection (4) and the efficacy rate was 100% with "excellent" (4) and "good" (7). Thus, both group A and B showed excellent results. AZT was also given to 24 cases for prophylaxis and all the cases showed prophylactic effect of AZT.4+ Bacteriologically AZT was deemed effective in 53 cases out of 56 (Group A) with identified pathogens "eradicated" and "unchanged" (2), thus the bacterial eradication rate was 96.2%. (3) A minor degree of loose feces was observed in 1 (1.3%) of 80 cases as a side effect. Abnormal laboratory test values found were eosinophilia (3 cases), elevation of GOT and GPT (2), platelet-increase (1), elevation of GOT (1), and thrombocytopenia.elevation of GOT.GPT.LDH (1). Every one of these was of a minor degree and transient. From the above pharmacokinetics and clinical results, standard dosage of AZT to neonates and premature infants should be in a unit dose of 20 mg/kg, twice daily to those with ages between 0 and 3 days, and 2 to 3 times daily to those with ages 4 days and above, by intravenous injection or intravenous drip infusion.

[Pharmacokinetics and clinical studies on aztreonam in neonates and premature infants (the second report). Study on effectiveness and safety in combination therapy using aztreonam and ampicillin. A study of aztreonam in the Perinatal Co-research Group].

Pharmacokinetics and clinical effects were studied in a combination therapy with aztreonam (AZT) and ampicillin (ABPC) in neonates and premature infants. The results obtained are summarized as follows. 1. Pharmacokinetics (1) Average serum concentrations at 30 minutes after one-shot intravenous injection of AZT 20 mg/kg and ABPC 25 mg/kg to a 4-7 days age-group of neonates were 41.3 (AZT) and 30.5 (ABPC) micrograms/ml, respectively. They gradually decreased to 14.7 and 2.7 micrograms/ml at 6 hours after the administration, but the concentration of AZT was always higher than that of ABPC. (2) Serum half-lives (T1/2) in the 4-7 days age-group were 3.61 hours for AZT and 1.42 hours for ABPC, thus T1/2 of AZT was longer. However, T1/2 of AZT was scarcely affected in the concomitant administration of ABPC. (3) Urinary excretion of AZT in the concomitant administration to the 4-7 days age-group was 52.7%, which was the same or a little higher comparing to that in AZT alone administration. 2. Clinical studies (1) AZT and ABPC were concomitantly administered to 160 cases and 133 cases were evaluated for efficacy. Pathogenic organisms were identified in 29 cases (Group A) and the efficacy rate was 86.2% (25/29). The number of cases in which pathogenic organisms were not identified (Group B) was 50 and in this group, the efficacy rate was excellent, 94.0% (47/50). AZT and ABPC were concomitantly administered to 54 cases for prophylaxis and in all the cases the administrations showed prophylactic effect. (2) Bacterial changes were confirmed in 21 of the 29 cases in which pathogenic organisms were identified initially and all of these 21 cases showed bacterial eradication, i.e., the bacterial eradication rate in the treatment was 100%. (3) There were 2 cases in which side-effects were observed among the analyzed 152 cases (1.3%). The side effects found were 1 case each of diarrhea and eruption. Abnormal laboratory values were found in 23 cases (15.9%), i.e., eosinophilia (9 cases), platelet-increase (4), elevation of GOT (4), elevation of GOT and GPT (3) and others (3). From the above pharmacokinetics and clinical results, the combination therapy of AZT and ABPC is considered to be one of the useful empiric antibiotic-therapies when pathogenic organisms are unknown in the infections of neonates and premature infants.

[A preclinical and clinical study of cefmenoxime in newborns].

1. Cefmenoxime (CMX) was administered with a dosage regimen of 20-25 mg/kg, 2-3 times daily (40-75 mg/kg/day) by intravenous drip over 30 minutes to 9 neonates with bacterial infections including purulent meningitis and septicemia. Clinical responses to the treatment were excellent in 7 and poor in 2. Bacteriological responses were "eradication of pathogens" from 8 of them except another patient with an infection due to Staphylococcus aureus. 2. Adverse reactions to CMX were observed in 6 of 18 neonates treated with the drug: diarrhea, oral thrush, and the elevation of S-GOT, S-GPT, LDH and alkaline phosphatase. None of the reactions, however, necessitated the discontinuation of the treatment. 3. Changes in blood concentrations of CMX in neonates with ages between 0 and 30 days were followed. These subjects included 16 mature neonates and 10 neonates with low birth weights. Intravenous drip infusion of 20 mg/kg of CMX over 30 minutes was immediately followed by peak blood CMX concentrations of 34.6-72.7 mcg/ml (mean +/- S.D.: 50.4 +/- 11.3 mcg/ml) in the mature neonates, and 22.3-78.2 mcg/ml (55.5 +/- 16.5 mcg/ml) in the neonates with low birth weight. Blood half-lives of the drug in the mature neonates were in the range from 1.7 to 20.7 hours (5.9 +/- 6.6 hours) in subjects with ages of 0-3 days, and 1.1-3.5 hours (2.0 +/- 0.8 hours) in subjects of 4-25 days. In neonates with low birth weight, they were 3.4-10.2 hours (7.2 +/- 2.7 hours) in subjects of 0-2 days, and 1.4-5.5 hours (3.0 +/- 1.5 hours) in subjects of 4-30 days. In other words, the blood half-lives of the drug tended to be longer in younger subjects. 4. Concentration of CMX in cerebrospinal fluid (CSF) were determined in a patient in acute stage with purulent meningitis caused by Mycoplasma hominis. Intravenous drip infusion of 80 mg/kg of CMX over 30 minutes was followed by CSF concentrations of 7.7-15.5 mcg/ml. 5. MICs of CMX for clinical isolates were determined. The drug was proved to have excellent antibacterial activities against Escherichia coli (3 strains) and group B hemolytic streptococci (2 strains) and these MICs were comparable to those of cefotaxime. The MIC of CMX for S. aureus (1 strain) was high at 25 mcg/ml with an inoculum size of 10(8) CFU/ml. This MIC value of CMX was higher than that of cefmetazole.

[Pharmacokinetic, bacteriological and clinical studies on imipenem/cilastatin sodium in neonates].

Pharmacokinetic, bacteriological and clinical studies on imipenem/cilastatin sodium (IPM/CS) were performed in neonates. The results were as follow: 1. A total of 27 patients consisting of 17 mature and 10 immature infants were treated with IPM/CS. Each dose was 20 mg/20 mg/kg, and it was administered 2 approximately 3 times daily, in a 1-hour intravenous drip infusion for 3 approximately 12 days. The clinical efficacy of IPM/CS in 10 patients with bacterial infections (2 with sepsis, 3 with suspected sepsis, 2 with pneumonia, 2 with urinary tract infection and 1 with acute omphalitis) was evaluated as excellent in all patients, with an efficacy rate of 100%. All 5 causative organisms found in 5 patients (Staphylococcus aureus in 1, Staphylococcus epidermidis in 1, Escherichia coli in 2 and Flavobacterium meningosepticum in 1) were eradicated. Among 27 patients administered IPM/CS, adverse reactions were observed in 2 patients. These were rash and diarrhea. As for abnormal laboratory test values, elevations of GOT and GPT were observed. 2. MICs of IPM against 14 clinical isolates (S. epidermidis 1, S. aureus 6, Streptococcus agalactiae 4, E. coli 1, Enterobacter cloacae 1 and F. meningosepticum 1) from neonatal patients with bacterial infections were examined. IPM showed good antibacterial activity comparable to that of cefotaxime against S. agalactiae; however, the activity against methicillin-resistant S. aureus was poor. 3. Serum levels of IPM and CS were investigated in a total of 22 patients consisting of 15 mature and 7 immature infants after 20 mg/20 mg/kg of IPM/CS was administered. IPM and CS produced peak serum levels at the end of the drip infusion. In mature infants, peak serum levels of IPM and CS were 31.8 micrograms/ml (17.1 approximately 59.0 micrograms/ml) and 59.9 micrograms/ml (35.6 approximately 99.0 micrograms/ml), respectively. In low birth weight infants, these were 25.0 micrograms/ml (16.8 approximately 41.8 micrograms/ml) and 55.2 micrograms/ml (33.8 approximately 82.4 micrograms/ml), respectively. Half-lives of IPM and CS were 1.0 approximately 2.7 hrs. and 0.9 approximately 7.4 hrs. in mature infants, and 1.6 approximately 3.0 hrs. and 1.3 approximately 9.7 hrs. in immature infants, respectively. Generally the longer half-lives were observed in the younger neonates. Serum levels of CS remained higher and half-lives of CS were longer than those of IPM. The pharmacokinetics in neonates were different from those in adults or children.(ABSTRACT TRUNCATED AT 400 WORDS)

[Pharmacokinetic and clinical evaluation of imipenem/cilastatin sodium in neonates and premature infants. A study of imipenem/cilastatin sodium by a perinatal co-research group].

Pharmacokinetics and clinical studies of imipenem/cilastatin sodium (IPM/CS), a combined preparation of a new carbapenem antibiotic and a dehydropeptidase-I inhibitor, respectively, were carried out in neonates and premature infants in a joint study by a co-research group. 1. Peak blood levels of IPM/CS when administered at 10 mg/10 mg/kg or 20 mg/20 mg/kg by 30- or 60-minute intravenous drip infusion were achieved at the end of infusion. A dose response was clearly observed between the doses and the peak levels achieved. 2. The areas under the blood concentration time curve (AUC) of CS were greater than those of IPM in most patients. Blood half-lives of IPM and CS tended to be longer in younger neonates and premature infants than in older subjects. The blood half-life of CS tended to be longer than that of IPM. 3. Cumulative urinary recovery rates of CS were greater than those of IPM, cumulative urinary recovery rates tended to be greater in older neonates and premature infants than younger subjects. 4. One hundred and thirteen patients were treated for bacterial infections with IPM/CS and 32 patients were treated prophylactically. Daily doses of IPM/CS ranged from 9 mg/9 mg/kg to 150 mg/150 mg/kg. 5. Clinical efficacies of IPM/CS were evaluated in a total of 56 patients with identified etiologic pathogens. The efficacy rate was 98.2% with 33 patients rated as excellent, 22 patients as good and 1 patient as fairly good. (Diagnoses were sepsis in 10 patients and meningitis in 2 patients, etc.) Fifty-seven patients with no identified etiologic pathogens were rated as excellent for 22 patients, good for 34 patients and fairly good for 1. The efficacy rate in these patients was 98.2%. Thirty-two patients were treated prophylactically and the results obtained were satisfactory. 6. Bacteriologically, the eradication rate was 94.5% in 56 patients; i.e., 52 were eradicated, 2 were decreased, 1 persisted and 1 was unknown. 7. Adverse effects were observed in 7 (4.4%) of 160 patients, i.e., 2 patients had diarrhea and 2 patients had rash, etc. Abnormal laboratory data considered related to the therapy occurred in 28 (17.6%) of 159 patients, with 10 patients with eosinophilia (6.3%) and elevation of GOT and/or GPT, etc. All these were non serious, and all values returned to normal after discontinuance of therapy. An abnormal prothrombin (PIVKA II) was observed in 1 of 10 patients tested.(ABSTRACT TRUNCATED AT 400 WORDS)

[Pharmacokinetics and clinical evaluation of ceftriaxone in neonates].

A parenteral cephem antibiotic ceftriaxone (CTRX) was studied for its pharmacokinetic features and clinical efficacy and safety in various infections in neonates including premature infants at 11 institutions associated with Japan Perinatal Infection Research Group. The following results obtained are summarized as follows. 1. Following single intravenous bolus injections with 10 and 20 mg/kg of CTRX, serum levels of the drug at 30 minutes post-dose 36-42 micrograms/ml and 46-76 micrograms/ml, respectively, and those at 12 hours post-dose were 10-14 micrograms/ml and 13-21 micrograms/ml, respectively, in a total of 105 neonates. Serum levels detected were on very gentle descending curves. 2. Half-lives (T 1/2) of the drug in serum were significantly prolonged in 0-3 day age groups of both mature and premature infants: it was especially long in premature infants with age of 0-3 days; i.e., 17.1 hours. There was no difference in T 1/2 between the 4-7 day and 8-28 day age groups. 3. Urinary excretion rates were 20-30% in the first 6 hours post-dose and 30-40% in 12 hours post-dose, in 80 neonates examined. 4. Clinical efficacy: Clinical efficacies were evaluated in 112 of 168 enrolled excluding infants with 90 days of age or older, who were treated for prophylaxis and unevaluable cases. The safety was evaluated in 161 of the 168. (1) Demographic background of the 112 cases: The 112 cases were composed of 89 neonates with ages of 28 days or younger, 21 premature infants, 57 males and 55 females. The drug was given to 102 of the cases by intravenous bolus injection, with 81 cases administered twice a day and 97 cases receiving 10-50 mg/kg a day. (2) Efficacy rate in the 112 cases: In 60 cases for whom causative pathogens were identified the efficacy rate was 90.0% in total (excellent: 31/60; good: 23/60); efficacy rates of 87.5% were obtained in 8 cases with purulent meningitis and 90.9% in 11 with septicemia. In 52 with causative pathogen not identified, the efficacy rate was 96.2% in total (excellent: 21/52; good: 29/52). (3) Adverse reaction: Adverse reactions were noted in 14 of the 161 cases where the safety was evaluated (8.7%). These reactions included diarrhea in 11, vomiting in 2 and exanthema in 1. Abnormalities in laboratory test values were observed in 25 of the 152 cases (16.4%). They included eosinophilia in 14, elevated GOT in 4 and thrombocytosis in 3 etc.(ABSTRACT TRUNCATED AT 250 WORDS)

[Fundamental study of amikacin in the newborn].

Amikacin (AMK) is one of the aminoglycoside antibiotics, derived from kanamycin A. It has a broad spectrum against Gram-negative rods but its usefulness is mainly in the efficacy against Gram-negative rods which do not respond to commonly used kanamycin and gentamicin. The efficacy and the safety of AMK have been confirmed in children and mature babies. In the trial reported here, we evaluated AMK in newborn. 1. AMK was administered to 13 mature and 8 premature babies via intramuscular injection or intravenous drip infusion for 30 minutes or 1 hour and its blood concentrations were determined. These administrations resulted in blood concentrations 4.47-9.67 mcg/ml with dosage levels 2.3 mg/kg (mean 6.92 +/- 1.66 mcg/ml), 5.86-26.1 mcg/ml with 5-6 mg/kg (mean 15.4 +/- 4.63 mcg/ml) and 27.5-37.7 mcg/ml with 7.5 mg/kg (mean 31.0 +/- 4.76 mcg/ml). Blood half-lives were 1.88 to 9.66 hours, showing longer half-lives in younger subjects. 2. Exchange transfusion (150-180 ml/kg) was performed in 5 mature babies and the variation of blood concentrations of AMK was studied. The study showed that blood concentrations of AMK after the exchange transfusion were 25.6-41.5% (mean 32.3 +/- 5.4%) of the levels detected before the transfusion.

[A pharmacokinetic and clinical evaluation of ceftazidime in neonates and premature infants. A study of ceftazidime in the perinatal co-research group].

Ceftazidime (CAZ) was evaluated for its pharmacokinetics and clinical usefulness in neonates and premature infants. The results obtained were summarized below. Following intravenous injection of CAZ 10 or 20 mg/kg to neonates and premature infants, dose response was observed in serum concentrations ranging from 5.1 to 21.9 micrograms/ml at 6 hours after the injection. The serum half-life tended to be longer in premature infants than in neonates; the half-life being longer for an infant with lower day-age. Urinary recovery rates during the first 6 hours after single administrations of 10 mg/kg of CAZ tended to be higher in neonates than in premature infants, and higher rates were observed in older infants. However, no noticeable difference was observed after the administration of CAZ 20 mg/kg. Clinical efficacy was evaluated in 99 neonates and 55 premature infants (156 infections), daily doses ranging from 21.1 to 246.4 mg/kg. Out of 105 cases of common infections, mainly 44 cases with causative organisms identified (including 17 of sepsis, 7 of pneumonia, 4 of purulent meningitis, 11 of urinary tract infections) were examined for the clinical efficacy. The efficacy of CAZ was excellent in 21, good in 18, fair in 1 and poor in 4, with the efficacy rate of 88.6%. In the remaining 61 cases, i.e., 37 with causative organisms unknown and 24 with signs of intrauterine infections, the efficacy rate was 95.1%. Other than these cases, additional 51 cases were given CAZ solely for prophylaxis of infections, and the results were found satisfactory. On the whole, clinical efficacy rate of CAZ was 94.9% in 156 cases. Out of the 44 cases examined for bacteriological responses, 38 were evaluated as 'eradicated', 3 'persisted' and 3 'unknown' with eradication rate of 92.7%. Replacement of organisms (superinfection) was observed in 3 cases. Out of 179 cases in which adverse effects were assessable, adverse effects were observed in a total of 4 cases (2.2%), i.e., 3 cases of diarrhea (1.7%) and 1 case of rash (0.6%), and abnormal laboratory findings were observed in a total of 14 cases (7.8%), i.e., increase in eosinophiles count in 8 (4.5%), elevation of GOT in 3 (1.7%), increase in platelet, elevation of GOT . GPT, and elevation of GOT . GPT . BUN in 1 case each (0.6%). None of them were severe and they were transient. Elevations of bilirubin and cases of positive PIVKA II associated with CAZ were not observed.(ABSTRACT TRUNCATED AT 400 WORDS)

[Clinical evaluation of ceftazidime in the treatment of neonatal infections].

Ceftazidime (CAZ) was evaluated for its safety and efficacy in 27 newborns. Four confirmed cases of bacterial infections were cured by the CAZ therapy (efficacy rate 100%). The CAZ was assessed as effective in sepsis (2) and urinary tract infections (2). Main pathogens which responded to CAZ were Escherichia coli, Enterobacter cloacae and Acinetobacter anitratum. As adverse effects, elevations of GOT and GPT (1 case) were found to be associated with the CAZ therapy. Half-lives of the serum levels in mature infants were 1.93-3.52 hours, and those in low birth weight infants were 2.92-4.17 hours. Penetration into the cerebrospinal fluid in 1 case of viral meningitis was satisfactory. The data suggest that CAZ is a safe and effective injectable antibiotic when used in newborn with infection caused by CAZ-susceptible bacteria.