Simultaneous determination of aminomethylbenzoic acid, cefminox sodium and etamsylate in human urine by capillary electrophoresis.

A sensitive and selective capillary electrophoresis method is developed, for the first time, for effective separation and simultaneous determination of aminomethylbezoic acid (PAMBA), cefminox sodium (CMNX) and etamsylate (ETM). The electrophoresis conditions were investigated and optimized. A 25 mM phosphate solution (pH 8.5) was used as a buffer and the peak area was determined with UV detection at 216 nm wavelength under 18 kV separation voltage. Under optimal conditions, the three drugs can be separated effectively. Good linearity was achieved in 3.13-150 microg/mL for PAMBA, 6.25-150 microg/mL for CMNX and 3.13-150 microg/mL for ETM, with the correlation coefficients of >0.999. The limit of detection (LOD) for PAMBA, CMNX and ETM was 1.04, 2.08 and 1.04 microg/mL, respectively. Their recoveries in human urine were in the range from 90.2% to 101% with the RSD (n=5) of 0.7-3.1%. The proposed method is simple, rapid and accurate, and provides the sensitivity and linearity necessary for analysis of the test drugs in human urine at clinically relevant concentrations.

Quantitative determination of semisynthetic cephamycins in human serum and urine by ion-exchange, reversed-phase and ion-pair chromatography.

High-performance liquid chromatographic methods have been developed for the determination of semisynthetic cephamycins: cefoxitin, cefmetazole and cefminox in human serum and urine samples. Serum samples spiked with each cephamycin were combined with an equal volume of methanol to remove proteins and, after centrifugation, and aliquot of the supernatant was analysed by ion-exchange, reversed-phase and ion-pair chromatography with hexadecyltrimethylammonium bromide as the ion-pairing agent. Urine samples were diluted, filtered and analysed by same chromatographic procedure. The cephamycins were detected by their ultraviolet absorbance (265-272 nm). It was possible to determine concentrations of cephamycins to 0.2 micrograms/ml in serum 2 micrograms/ml in urine samples with a good level of reproducibility and accuracy.

[Excretion of antibiotics into bile and urine in patients with external cholecystostomy done in order to treat obstructive jaundice].

Biliary and urinary concentrations and recoveries of 3 different antibiotics (piperacillin (PIPC), cefbuperazone (CBPZ) and cefoperazone (CPZ], after intravenous bolus injection were studied using the crossover method with external cholecystostomies done in order to treat obstructive jaundice due to complete obstruction of the lower biliary tract; the concentrations of antibiotics in bile and urine were determined by means of a high performance liquid chromatography method. Drug concentrations and recoveries in the bile after intravenous injection of these antibiotics were at levels in the order of CPZ greater than CBPZ greater than PIPC. Since our patients were inflicted with various malignancies which made them impaired in terms of biliary excretion of antibiotics, the concentrations of those drugs in the bile were lower than those previously reported by several investigators. However, CBPZ and CPZ showed sufficient levels of excretion into the bile and their amounts were high enough when compared to the value of MIC 80% reported recently against Escherichia coli and Klebsiella pneumoniae, which are known to be main pathogens of biliary system infections. The excretion of CPZ into the bile was invariably found to be 2 times or more as high as the other 2 drugs tested. Concentrations and recoveries of the 3 antibiotics excreted into urine were similar to the cefotaxime excretion, of which into urine had been reported to be excellent. Thus, CBPZ and CPZ appeared to be effective against biliary system infections, even with blockage of antibiotics excretion into the bile.

Cefotetan pharmacokinetics in volunteers with various degrees of renal function.

Twenty-six volunteers with various degrees of renal function were given a single 1-g dose of cefotetan intravenously over 30 min. Concentrations of cefotetan and cefotetan tautomer in plasma and urine were determined by high-performance liquid chromatography. The pharmacokinetic parameters for cefotetan were calculated according to a two-compartment open model. The mean plasma cefotetan concentration at the end of the intravenous infusion did not vary with renal function and ranged between 122 and 126 micrograms/ml. The mean terminal half-life was 4.2 h in normal volunteers and 9.9 h in volunteers with moderate renal impairment. There was a significant linear correlation between the systemic clearance of cefotetan and creatinine clearance. The cumulative amount of cefotetan excreted in the urine over 24 h in normal volunteers was approximately 49% of the dose, but this was reduced in volunteers with moderate renal impairment. The mean urinary cefotetan concentrations generally peaked during the 2- to 4-h interval after dosing. Cefotetan tautomer was sporadically detected in the plasma and urine of approximately 50% of the volunteers. The mean plasma cefotetan tautomer concentrations and mean total cumulative urinary recoveries of cefotetan tautomer were only minimal compared with those for cefotetan. The mean percentage of the dose excreted in the urine as cefotetan tautomer was not significantly affected by the degree of renal impairment. Recommendations for the dosing of cefotetan in renal-impaired patients are given.

Cefmetazole: clinical evaluation of efficacy and safety in Japan.

During the period February 1980-March 1982, clinical evaluation was carried out on 23,855 cases given cefmetazole (CMZ) in 3,916 medical treatment centres in Japan. The drug was found to have superior efficacy and to be of value for all age groups, ranging from infants and small children to the elderly, in infections due to Gram-positive cocci, Gram-negative bacilli and anaerobic bacteria sensitive to this drug. Experiments were also conducted to elucidate the mechanism of development of the disulfiram-like reaction found in cephems with a methyltetrazolylthiomethyl group at the 3 position, i.e., cefmetozole (CMZ), cefoperazone (CPZ) and latamoxef (LMOX). These experiments provided clear evidence that the reaction is due to a rise in the blood concentration of acetaldehyde, as a result of inhibition of acetaldehyde dehydrogenase activity caused by these cephems. The extent of increase in the blood concentration of AcH is proportional to the urinary excretion rate of mercaptomethyltetrazole (Me-TZ), being in the order CPZ greater than LMOX greater than CMZ. This order is believed to be due to the extent of distribution in bile by various antibiotics and to their stability in the tissue fluids.

[Postoperative evaluation of renal function from the aspect of urinary concentration of cefmetazole in infants and children with vesicoureteral reflux and hydronephrosis. I].

The urinary excretion of cefmetazole (CMZ) which was administered intravenously from both kidneys (affected side and normal side) was studied separately after surgery in 11 infants and children (10 cases of vesicoureteral reflux (VUR) and 1 case of hydronephrosis due to pelviureteric obstruction). In kidneys with VUR of grade IIb to III degree, urinary concentration of CMZ showed rather higher than that we expected from their creatinine clearance. On the contrary in kidneys with VUR of grade IV degree and hydronephrosis, urinary concentration of CMZ showed rather lower compared to their creatinine clearance.

High-performance liquid chromatographic analysis of cefotetan epimers in human plasma and urine.

Cefotetan, a new broad-spectrum 7 alpha-methoxycephalosporin antibiotic, was assayed in plasma and urine by means of reversed-phase high-performance liquid chromatography. Commercially available cefotetan exists in two epimeric forms. The procedure described allows the separation and quantitation of both epimers. For the first time a different pharmacokinetic behaviour (t1/2 = 3 h versus 4 h) for each epimer after intravenous injection to healthy volunteers is demonstrated. It is assumed that one epimer is bound to a greater extent to serum proteins and is therefore responsible for the differences observed. As both epimers exhibit similar antibacterial activity, it seems doubtful whether these differences would have clinical significance. Iothalamic acid was determined simultaneously as a marker of kidney function.

[Microbiological, kinetic and clinical study on a new cephamycin: cefotetan]. / Ricerca microbiologica, cinetica e clinica su una nuova cefamicina: cefotetan.

Microbiological, kinetic and clinical studies were conducted on a new cephamycin, cephotetan. In vitro the antibiotic was found to be very effective against all strains tested. It had a particularly strong action against Gram negative bacteria too. Kinetically speaking, an intravenous bolus produced a high plasmatic concentration with a half life of about 4 hours. Elimination via the kidneys was fastest in the first 3 hours after administration (49.82%) and the slowed down. 82.76% of the dose administered was excreted within 24 hours. This antibiotics is particularly indicated in cases of urinary, respiratory and biliary infections.

Moxalactam--absorption, excretion, distribution, and metabolism.

Levels of moxalactam in serum of healthy volunteers after single intramuscular injection, slow bolus intravenous injection, or intravenous infusion were proportional to the dose given. After intravenous bolus injection of 1 g of moxalactam, the peak serum level was 201.0 micrograms/ml, the half-life (beta-phase) was 126 min, and the cumulative urinary excretion during a 10-hr period was 90.5% of the dose. The values for cefazolin in the same volunteers were similar to those for moxalactam. No accumulation of the drug in serum was found even after multiple intravenous injections of 1 g every 12 hr for five days. Probenecid administered orally did not significantly affect levels of moxalactam in serum or urinary recovery, an observation which suggests that renal excretion of moxalactam takes place mainly through glomerular filtration. The serum half-life (beta-phase) of moxalactam in subjects with a creatinine clearance rate of less than or equal to 10 ml/min was markedly prolonged. Concentrations of moxalactam in bile were higher than those of cefazolin in a crossover study. Concentrations in sputum were 1.84-2.11 micrograms/ml in individuals given 1 g by intravenous slow bolus injection. No active metabolite of moxalactam was detected in plasma or urine.

Absorption, excretion, and clinical efficacy of moxalactam in pediatric patients.

Absorption and excretion of moxalactam were studied in 58 children between two and 14 years of age. Mean serum levels reached peaks of 96.6 and 76.0 micrograms/ml 15 min after intravenous injection of 20 and 10 mg of moxalactam/kg, respectively. The respective serum half lives were 103 and 83 min. Mean serum levels after intravenous drip infusion over a 1-hr interval reached peaks of 71.4 and 39.8 micrograms/ml at the end of the infusion of 20 and 10 mg/kg, respectively. The respective serum half lives were 103 and 94 min. Mean cumulative urinary recovery of the administered dose for the 6-hr interval after intravenous injection or drip infusion was approximately 73%. Among the patients from whom pathogens were isolated, satisfactory clinical response was obtained in 11 (92%) of 12 patients with meningitis, 4 (80%) of 5 patients with septicemia, all 9 patients with bronchitis, 32 (91.4%) of 35 patients with pneumonia, 33 (91.6%) of 36 patients with urinary tract infections, and all 8 patients with lymphadenitis or skin and soft-tissue infections. In all of the nine patients with meningitis for whom levels of the drug in cerebrospinal fluid were determined, levels of moxalactam were much higher than the minimal inhibitory concentrations for the pathogens, and these levels were associated with prompt clinical and bacteriologic responses. Adverse reactions were noted in only four of 279 treated patients.

High-performance liquid chromatographic analysis of a new beta-lactam antibiotic, 6059-S (moxalactam).

Reversed-phase high-performance liquid chromatography was applied to the quantitative determination of a new beta-lactam antibiotic, 6059-S, ant its R- and S-epimers were resolved. The procedure was also applied to pharmaceuticals and human urine samples. Chromatographic separation was effected on a bonded hydrophobic stationary phase with two mobile phases: methanol-phosphate butter for the resolution of the epimers and methanol-tetra-n-butylammonium phosphate for the quantitation of 6059-S. For the determination of 6059-S in human urine, the latter mobile phase was used successfully without interference by the other urine components. An in vivo experiment was conducted by administering intravenously 1 g of 6059-S to seven volunteers and analysing their urine by chromatographic and microbiological assays, and a comparison of the results gave a correlation coefficient of 0.9954. One-compartment model analysis of the time-course data revealed that 6059-S was excreted in urine intact with a rate constant of 0.433h-1.

Determination of moxalactam in human body fluids by liquid chromatographic and microbiological methods.

High-performance liquid chromatographic methods for determination of the isomers of moxalactam in plasma and urine have been developed. Conventional reverse-phase chromatography was used for plasma assays, and an ion-pairing reagent was included for urine assays. Detection limits were 1.5 micrograms/ml of plasma and 7.5 micrograms/ml of urine. The high-performance liquid chromatographic assays were extensively compared with a microbiological assay (detection limit, 1 microgram/ml), using samples from human volunteers to whom moxalactam had been administered as well as plasma and urine from untreated humans, to which moxalactam was added. The correlations between the assays were quite good, but the precision and accuracy of the high-performance liquid chromatographic methods were superior. Both types of assays were used in a study of the stability of moxalactam-containing samples at various temperatures.

[Examination of blood levels and urinary excretion of cefmetazole in the mature and immature neonates (author's transl)].

1. Cefmetazole was administered to mature and immature neonates for the purpose of treatment and prophylaxis of infections, and the blood level was examined. The mean blood level (moni-trol I standard) of cefmetazole after a single administration, 20 mg/kg intravenously, were 63.9 mcg/ml in 0 to 3 days old neonates and 57.4 mcg/ml in 4 to 7 days old neonates after 30 minutes, and 24.2 mcg/ml and 12.4 mcg/ml, respectively, after 6 hours. 2. The mean half-life of the blood level was 5.42 hours in 0 to 3 days old neonates and 2.55 hours in 4 to 7 old neonates. 3. The urinary excretion was varied, but approximately 80% of the administered dose seemed to be excreted during 0 to 12 hours. 4. Cefmetazole is seemed to be clinically effective by a single dose of 20 mg/kg giving twice daily in every 12 hours in 0 to 3 days old neonates, a dose of 20 mg/kg giving three times daily in every 8 hours in 4 to 7 days old infants, and a single dose of 20 mg/kg giving 3 to 4 times in every 6 to 8 hours in older than 8 days old neonates.

[Studies on absorption and excretion of cefmetazole in neonates and excretion into the bile of infants with congenital biliary atresia (author's transl)].

This is studies concerning the absorption and excretion of cefmetazole in neonates and the excretion into the bile of infants with congenital biliary atresia. 1. The concentration of cefmetazole was measured in the serum and urine of 2 neonates at the postoperative period. 2. The concentration measured in the serum showed a level similar to those of cases in pediatrics at other institutes regardless of the operation. 3. The recovery value of cefmetazole in the urine of the neonate is not different from those of other institutes even if it is a postoperative case, provided that the urine quantity is maintained. 4. Excretion of cefmetazole into the urine and bile was measured in 2 cases of congenital biliary atresia after the biliary diversion. 5. The concentration of cefmetazole in the bile of infants with congenital biliary atresia is lower than those of adults. It follows that the recovery percentage in the bile is low but the converse was true in the urine recovery. This seemed to be due to liver dysfunction that are characteristic in congenital biliary atresia. However, the concentration of cefmetazole in the bile was sufficient to obtain effective therapeutic level.

[Basic and clinical examinations of CS-1170 in pediatrics (author's transl)].

1. CS-1170 was administered for the purpose of prophylaxis during cardiac catheterization in patients with heart disease, and its blood levels were measured. 2. The mean blood level (Moni-Trol I standard) after one intravenous shot of 20 mg/kg was 53.6 mcg/ml in catheterized children aged below 6 and 66.9 mcg/ml in catheterized children aged above 10 at 30 minutes, and 1.95 mcg/ml and 5.2 mcg/ml respectively at 6 hours. 3. The mean half life of the blood level was 1.09 hours in catheterized children aged below 6, 1.37 hours in catheterized children aged above 10, and 0.71 hours in infections children. 4. The urinary excretion seemed satisfactorily high although there was a great variation. 5. The clinical efficacy was 88.9%. 6. The bacteriological efficacy was 100% for E. coli, Klebsiella, Proteus mirabilis and Staphylococcus aureus and was 0% for Staphylococcus epidermidis. 7. Although GOT and GPT were elevated in one case as a side effect, they rapidly returned to normal after discontinuation of administration.

[Pharmacokinetics and results of clinical administration of CS-1170. I. Pharmacokinetics of CS-1170 (author's transl)].

(1) When 20.8 approximately 34.7 mg/kg body weight of CS-1170 were instilled intravenously for 30 minutes to one hour, peak levels were obtained on completion of the intravenous drip in the range 85.7 approximately 1,117.3 microgram/ml. (2) The half life was 22 approximately 49 minutes which is very rapid. (3) The kidney clearance was 6.8 approximately 104.8 ml/min. (4) The total clearance was 5.9 approximately 111.5 ml/min, showing correlation with the kidney clearance. (5) The apparent distributional capacity was 0.3 approximately 4.3 liters, showing a strong correlation with body weight.