Familial hypercholesterolemia with cholesteryl ester transfer protein deficiency.

A 21-year-old male was clinically diagnosed with familial hypercholesterolemia (FH) by the manifestations of hypercholesterolemia, tendon xanthoma and family history of premature coronary heart disease. Low density lipoprotein receptor gene was analyzed in attempt to determine a possible point mutation. The normal sequence was partially preserved, and the patient was genetically diagnosed as a heterozygote of FH. In addition, screening for two cholesteryl ester transfer protein (CETP) gene mutations common to Japanese revealed the patient to be a heterozygote of CETP deficiency. A complication of two influential mutations for atherosclerotic ailments was genetically ascertained.

Effect of glibenclamide on ischemic canine myocardium with glucose infusion.

Glibenclamide, an ATP-sensitive K (K ATP) channel blocker, worsens the ischemia-induced metabolic derangement in the heart through inhibition of K ATP channels. We examined whether the hypoglycemic effect of glibenclamide was involved in the worsening of myocardial energy metabolism during ischemia. Pentobarbital-anesthetized dogs were subjected to 15-min ligation of the left anterior descending coronary artery. Either vehicle (dimethyl sulfoxide, DMSO) or glibenclamide (1 mg/kg) was injected i.v. 10 min before the ligation. In half of the animals given glibenclamide, glucose was continuously infused at 3 mg/kg per min immediately after glibenclamide injection. Glibenclamide increased the serum insulin level and decreased the blood glucose level. Glucose infusion completely abolished the hypoglycemia due to glibenclamide. Glibenclamide enhanced the decrease in ATP and total adenine nucleotides and increase in tissue lactate caused by ischemia. Glucose infusion did not cancel the augmentation of ischemia-induced alterations of myocardial energy metabolism caused by glibenclamide. These results suggest that K ATP channels directly play an important role in endogenous mechanisms of myocardial protection against ischemic damage.

Enhancement of ischemic myocardial metabolic derangement by glibenclamide.

We examined whether opening of the ATP-sensitive potassium (KATP) channels in the ischemic myocardium plays an important cardioprotective role during ischemia. Dogs were anesthetized with sodium pentobarbital (30 mg/kg, i.v.). Sixty minutes after treatment of the dog with glibenclamide (0.3 or 3 mg/kg, i.v.), the LAD was ligated. At 3 or 15 min after LAD ligation, left ventricular tissue was taken from the ischemic region to measure tissue metabolite levels. After ischemia, the tissue levels of ATP and creatine phosphate decreased to 49-74% and 26-34%, respectively, and lactate level increased to 380-660%. Ischemia (either 3 or 15 min) increased the levels of G6P and F6P and decreased the FDP level, indicating the inhibition of glycolysis. Glibenclamide at either dose decreased the level of blood glucose by 20-30% and increased the blood insulin level twice. The decrease in ATP and increase in lactate due to ischemia were significantly enhanced by glibenclamide at a dose of 3 mg/kg. The increase in G6P due to 15 min of ischemia were also enhanced significantly by 0.3 and 3 mg/kg of glibenclamide. Glibenclamide worsened the metabolic alterations produced by ischemia. These results suggest that KATP channels that can be inhibited by glibenclamide may perform some functions in the ischemic myocardium.

Pharmacokinetics of the digoxin-quinidine interaction via mixed-effect modelling.

It was the purpose of this study to evaluate the effect of quinidine administration on the population estimates of the volume of distribution (Vdpop) and clearance (CLpop) of digoxin. The data collected on 94 patients included 230 measured serum digoxin concentrations, height, age, sex, weight (wt), serum creatinine, history of digoxin and quinidine administration and the presence or absence of congestive heart failure (CHF). Using the NONMEM software program, estimates were obtained for CLpop and Vdpop. Variables tested for inclusion in the CLpop model were creatinine clearance (CLCR), CHF, wt, ideal bodyweight, quinidine (QUIN) [both as a discrete variable and in a dose-dependent manner], and body surface area. Variables tested for inclusion in the Vdpop model were CLCR, wt, ideal bodyweight, body surface area and quinidine. During model building a p-value of 0.05 was chosen for variable inclusion. The final model was as follows: CLpop (L/h) = (3.1 + 0.0516 x CLCR) x QUIN Vdpop (L) = (4.03 + 0.0832 x CLCR) x wt F = 0.82 where F is bioavailability. In the above, QUIN is 0.567 if quinidine is being concurrently administered and 1.0 if it is not. The coefficient of variation (CV) of CLpop was 44% while that of Vdpop was 48%. The residual intrasubject CV was 26%. These results compare favourably with previously derived methods of estimating digoxin CLpop and Vdpop but may improve on those methods due to the inclusion of quinidine in the model. These better estimates should result in improved initial dosage of digoxin.

Dichloroacetate attenuates myocardial acidosis and metabolic changes induced by partial occlusion of the coronary artery in dogs.

The present study was undertaken to examine whether dichloroacetate, which inhibits pyruvate dehydrogenase kinase and, therefore, increases the activity of pyruvate dehydrogenase, attenuates myocardial acidosis and metabolic changes induced by coronary occlusion. In dogs anesthetized with pentobarbital, the left anterior descending coronary artery was incompletely occluded to reduce the left anterior descending flow to a half to one third of the original flow (partial occlusion) to produce myocardial (regional) ischemia. Partial occlusion was continued for 90 min, and a bolus injection of saline or dichloroacetate was made intravenously 30 min after the onset of occlusion. Partial occlusion decreased myocardial pH significantly. An injection of dichloroacetate (150 mg/kg) increased myocardial pH that had been lowered by partial occlusion. Myocardial metabolites were measured in other dogs. Partial occlusion decreased the myocardial levels of adenosine triphosphate, creatine phosphate and energy charge potential, and increased that of lactate significantly, without affecting the myocardial levels of pyruvate and nonesterified fatty acids. Dichloroacetate attenuated the ischemia-induced changes in the myocardial levels of adenosine triphosphate, creatine phosphate, energy charge potential and lactate. These results indicate that dichloroacetate attenuates the myocardial acidosis and metabolic changes during coronary partial occlusion.

[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.

[Effects of cibenzoline on myocardial ischemia].

The effect of cibenzoline, an antiarrhythmic drug, on myocardial ischemia was studied in the anesthetized open-chest dog. Ischemia was induced by completely ligating or partially occluding the left anterior descending coronary artery. The levels of ATP and creatine-phosphate decreased, and the ADP and AMP levels increased during ischemia. The level of glycogen was also decreased, and that of lactate was increased by ischemia, resulting in myocardial acidosis. Pretreatment with either 2 mg/kg or 8 mg/kg of cibenzoline prevented the decrease in ATP level and the increase in lactate level. These results suggest that cibenzoline reduces the influence of ischemia on the myocardium.

[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.

[A case of subacute thyroiditis associated with acute hepatitis].

We report one case of subacute thyroiditis associated with acute hepatitis, which is histopathologically diagnosed. A 43-year-old woman visited our hospital with chief complaints of fever, sore throat and anterior neck pain. Thyroid gland was found to be swollen and tender. Laboratory findings gave high ESR and positive test for CRP. High values of T3, T4 and RT3U indicated that the patient had hyperthyroidism. However no autoantibodies against thyroglobulin and microsome were found. High activities of serum AIP, LAP and gamma-GTP were observed. Serum GOT and GPT activities increased moderately. AIP type 2 was dominant in zymograms. Histopathological findings of liver specimen obtained by needle biopsy showed ballooning degeneration of hepatocytes with a slight focal necrosis and hyaline bodies. In addition bile plugs were observed in some biliary tubules. These findings were consistent with those of acute hepatitis. After three months all laboratory data were found to be within normal ranges and no recurrence has been observed. Subacute hepatitis associated with liver dysfunction is considered to be relatively frequent. However very few reports have been published on the case in which histopathological evidence for acute hepatitis was presented.

[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.

[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.