A specific and rapid HPLC assay for the determination of cefroxadine in human plasma and its application to pharmacokinetic study in Korean.

A specific and rapid high performance liquid chromatographic (HPLC) method with UV detection (254 nm) was developed for the determination of cefroxadine in human plasma. The sample extraction was performed by a simple procedure, vortexing and centrifugation of sample following addition of 60% trichloroacetic acid. Cephalexin was used as an internal standard (I.S.). The HPLC analysis was carried out on a Capcell Pak C18 analytical column with a mobile phase of 50 mM ammonium formate buffer/pH 3.5 and acetonitrile (90:10, v/v). No interference was observed near the peaks of cefroxadine and I.S. The calibration curve was linear over the range of 0.5-40 microg/mL and the lower limit of quantification (LLOQ) was 0.5 microg/mL. The method was validated with excellent sensitivity, accuracy, precision and stability. This assay was successfully applied to determine the pharmacokinetic parameters of cefroxadine in Korean healthy volunteers after an oral administration of two 250 mg cefroxadine capsules. As a result, the plasma half-life was 1.00+/-0.26 h and the mean AUC(0-6 h) was 46.25+/-6.41microgh/mL. The maximum plasma concentration (C(max)) of 17.62+/-4.87 microg/mL reached 1.44+/-0.39 h after administration.

Synthesis and antibacterial activity of cephradine metal complexes : part II complexes with cobalt, copper, zinc and cadmium.

Cephradine, the first generation cephalosporin, is active against a wide range of Gram-positive and Gram-negative bacteria including penicillinase-producing Staphylococci. Since the presence of complexing ligand may affect the bioavailability of a metal in the blood or tissues, therefore, in order to study the probable interaction of cephradine with essential and trace elements present in human body, cephradine has been reacted with cobalt, copper, zinc and cadmium metal halides in L:M ratio of 2:1 in methanol and the products recrystallized from suitable solvents to pure crystals of consistent melting points. Infrared and ultraviolet studies of these complexes were carried out and compared with ligand. Magnetic susceptibility studies of these complexes were also carried out showing their paramagnetic behavior. From the infra red studies and elemental analysis of the complexes, it has been shown that the drug molecule serves as a bidentate ligand coordinating through both its carboxylate at C-3 and beta-lactam nitrogen and the metal having a square planar or octahedral geometry. To evaluate the changes in microbiological activity of cephradine after complexation, antibacterial studies were carried out by observing the changes in MIC (minimum inhibitory concentration) of the complexes and compared with the parent drug by measuring the zone of inhibition of complexes and compared with the parent cephalosporin against both Gram-positive and Gram-negative organisms. For MIC observation, serial dilution method was employed and zone series were determined by disk diffusion method. Our investigations reveal that formation of complexes results in decrease in antibacterial activity of cephradine and MIC values are increased.

Determination of the thermodynamic ionization constants of cefroxadine.

The values of the thermodynamic ionization constants of the carboxylic (pK = 3.30 +/- 0.02) and amine (pK = 7.00 +/- 0.06) groups of cefroxadine were determined at 35.0 degrees C using potentiometric data. The apparent ionization constants of these groups were also determined at 35.0 degrees C, and at different values of ionic strength.

Antibacterial effects of cefroxadine, cephalexin and cephradine in a new in vitro pharmacokinetic model.

A pharmacokinetic model has been developed, by means of which all possible time courses of the concentrations of antibiotics in the plasma of treated individuals can be exactly simulated in vitro without diluting the test organism and affecting the growth curves. Equieffective concentrations in the system corresponded to the plasma concentrations in man produced by cefroxadine in a single oral dose of 250 mg and cephalexin and cephradine in a single oral dose of 500 mg.

Synthesis and biological activity of (2-hydroxy-1-naphthyl)-methylamino acetamido-epicillin and cephradine, and (2-hydroxy-1-naphthyl)-methylacetamido 6-APA.

Two new penicillins and a new cephalosporin have been synthesized by condensing 2-hydroxy-1-naphthaldehyde with epicillin, 6-aminopenicillanic acid and cephradine, and subsequently reducing the SCHIFF bases with NaBH4. The antimicrobial activities of these compounds are also described.

Isolation and structural elucidation of an impurity of cefradine.

An impurity of unknown identity was isolated from commercial cefradine by liquid chromatography on poly (styrene-divinylbenzene) with HOAc (0.01 M)-CH3CN (94:6, v/v) as the mobile phase. The structure was elucidated as 4',5'-dihydrocefradine using nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). The structure was confirmed by comparison with the chromatographic retention characteristics and photodiode-array detected ultraviolet spectrum of the synthetic compound and with its infrared, NMR and MS spectra. The presence of 4',5'-dihydrocefradine in cefradine has not been described previously.

In-vitro evaluation of a new oral cephalosporin, cefroxadine (CGP 9000).

The in vitro activity of cefroxadine was studied and found to be at least comparable to that previously reported for cefalexin and cefradine. The activity of cefroxadine was superior to that of amoxicillin against tested isolates. Time-killing studies showed that the addition of 4 X minimum inhibitory concentration (MIC) of cefroxadine to growing cultures reduced viable counts by 4 log units within a 3 h incubation. A diffusion test with a 30 microgram cefroxadine disk produced acceptable interpretive results with tentative zone size breakpoints of less than or equal to 14 mm for resistance and greater than or equal to 17 mm for susceptibility.

Cefroxadine in the treatment of children affected by respiratory and ENT diseases. A multicentre study involving 1072 in-patients.

In this multicentre trial, 1072 hospitalized children, 573 boys and 499 girls (847 of whom were aged less than 6 years), affected by respiratory tract (376 patients) or ENT (696 patients) infections were treated for 10 days with cefroxadine per os, at an average dose of 650 mg/day (325 mg every 12 h corresponding to 25 mg/kg b.w.). Most patients (1047; 97.7%) completed the trial, while 25 patients were withdrawn from the study (20 patients for viral diseases and 5 for side-effects). Of the patients affected by respiratory tract infections, 361 completed the trial and 342 of them (94.7%) were cured in 6.0 days on average. Of the patients affected by ENT infections, 686 completed the trial and 649 of them (94.6%) were also cured in an average of 6.0 days. In the two groups the signs and symptoms of the disease significantly (p less than 0.001) decreased by the end of the study. Some patients (80; 7.6%) complained of side-effects, mainly gastric discomfort (4.9%), skin rash (2.2%) and glossitis (0.5%). In conclusion, cefroxadine exerts a satisfactory antibacterial action with only a few days of treatment, and it appears to be very well tolerated.

Comparison of microbiological and high pressure liquid chromatographic assays of the new cephalosporin cefroxadine.

A method employing high pressure liquid chromatography has been developed for the new cephalosporin cefroxadine (CGP 9000). This uses Lichrosorb RP-8 5 micron as the stationary phase and 2 mM phosphoric acid mixed with methanol in the ratio 72:28 for the mobile phase. The retention time is 6.5 minutes. The procedure has a correlation with microbiological assay of r = 0.968 for sera after oral dosage and r = 0.944 after intravenous doses. Correlations in sera from each individual has ranged from 0.957 to 0.998. A protein binding of 5 per cent was found for a concentration of 10 microgram/ml and of 7.5 per cent at 2 microgram/ml. The HPLC method had a recovery of 92.5 at a low level of 2 microgram/ml and 95 per cent at 10 microgram/ml.

Comparison of continuous, constant rate enteral tube feeding in supine patients to bolus food intake in ambulatory, healthy subjects regarding bioavailability of perorally administered cefroxadine.

Stabilized, bedridden, inactive trauma patients on enteral nutrition via continuous, constant rate tube feeding (2 different formulas) were given a single dose of cefroxadine p.o. There were no differences in the pharmacokinetic parameters between the groups on different enteral nutrition. These patients were compared to cefroxadine absorption in ambulatory healthy subjects after a standardized meal (bolus-fed). The mean residence time was significantly longer in the patients, and the extent of absorption was slightly reduced with one enteral nutrition formulation and significantly reduced with the other. The other pharmacokinetic parameters were not significantly different. The difference is believed to be caused by reduction in splanchnic blood flow in the immobilized patients, weakening of migrating motor complex due to tube feeding and the lower temperature (4 degrees C) of enteral nutrition.

Peroral absorption of cefroxadine in patients within the first day after severe trauma: comparison to cefroxadine pharmacokinetics in fasted, healthy volunteers.

Peroral absorption of cefroxadine given to 7 24-h fasted trauma patients by nasogastric tube within the first day of admission was compared to that obtained in fasted healthy volunteers. The trauma patients exhibited significantly lower Cmax and reduced AUC. Even though rate and extent of bioavailability cannot be determined from these two different population groups since the total clearance must be assumed to be different in patients and healthy subjects, a reduced bioavailability is assumed based on pathophysiologic reflections.

[Cephalosporins and enzymuria]. / Cefalosporine ed enzimuria.

Urinary enzyme excretion was studied in 56 patients treated with cephalosporins in order to evaluate their potential nephrotoxicity. Only in 4 out of 56 patients (7%) was increased NAG, gamma-GT, AlP excretion seen. A rapid return to normal values was observed just after the end of the therapy.

[Clinical study on a new cephalosporin: CGP 9000 (cefroxadine)]. / Ricerca clinica su una nuova cefalosporina: CGP 9000 (cefroxadina).

CGP 9000 (cefroxadine), a new cephalosporine derived from N-acyl-3-alkoxy-7-amino-3-cefem-4-carboxylic acid for exclusively oral use, has been experimented on 67 patients, 41 adults and 20 children. CGP 9000 appeared to possess good therapeutic activity, even in low doses: its rapid absorption and moderate sero-protein bond are a guarantee of an immediate and almost total bioavailability.

[Study of cefroxadine in pediatrics regarding clinical efficacy and serum levels (author's transl)].

Basic and clinical evaluations of cefroxadine were carried out in children, and the following results were obtained. 1. Cefroxadine 20 mg/kg was administered to 9 children with heart disease for the prophylaxis against infections before undergoing cardiocatheterization and cardioangiography, and serum levels were determined. Peak levels reached after 30 minutes in 4 of the 9 cases, with a mean peak level of 22.5 mcg/ml and after 1 hour in 5 cases, with a mean peak level of 16.2 mcg/ml. Half life was 3.1 hours in the former group in a 6-hour blood sampling (1.04 hours in a 2-hour sampling) while in the latter group it was 1.37 hours. 2. Clinical responses were evaluated in 56 children comprising 23 cases of pharyngitis, 8 of tonsillitis, 13 of scarlet fever, 10 of urinary tract infections and 2 of impetigo. Fifty of these cases had excellent and good responses showing a efficacy rate of 89.3%. 3. From 42 of the cases, 43 strains were isolated as causative organisms. Major organisms included 27 strains of S. pyogenes, 9 of E. coli and 3 of S. aureus. As for bacteriological responses, all strains were eradicated. 4. No severe side effects were observed except for diarrhea of 1 cases and eosinophilia of 2 cases. Furthermore, no children refused to take cefroxadine dry syrup.

[Clinical studies with cefroxadine dry syrup in the field of pediatrics (author's transl)].

The clinical and pharmacokinetic studies of cefroxadine (CXD) dry syrup were conducted, and the following results were obtained. 1. A single dose of CXD either 10 mg/kg or 20 mg/kg was given to 2 patients each, and serum levels were peaked in the range of about 10 to 11 microgram/ml. 2. About 30 mg/kg of CXD per day was administered to 47 infants and children (37; upper and lower respiratory tract infection, 3; urinary tract infection, 7; Others) aged from 6 months to 8 years and 1 month weighing 8 to 29 kg, and a 97.8% (44 out of 45) of clinical response was obtained except for 2 cases whose efficacies were uncertain. 3. As the drug-induced side effects, only transient loose stool was observed in 2 cases. This, however, allowed to continue the treatment.

[Clinical studies on cefroxadine in the field of pediatrics (author's transl)].

Cefroxadine dry syrup was administered to 57 children with acute febrile respiratory tract infections and 2 children with scarlet fever in the dose of 40 mg/kg/day q.i.d. for 2 approximately 7 days. 65 strains of organism were isolated as pathogen from the 59 patients, and 50 of the 65 strains (76.9%) showed bacteriologically good responses. Clinically, 55 children (93.2%) had good response. Out of 63 strains isolated from the 57 cases with respiratory infections, 48 strains (76.2%) showed good bacteriological response. As for the type of pathogen, all strains of Staphylococcus aureus, 86.4% of Streptococcus haemolyticus and 90.0% of Streptococcus pneumoniae had good response, but as for Haemophilus influenzae it was only 47.6%. In one child, Streptococcus pneumoniae appeared during cefroxadine treatment in addition to the preexisting Haemophilus influenza. From the 4 children having no response for their respiratory infections, H. influenzae were isolated in 3 cases and Streptococcus haemolyticus was isolated in 1 case, before starting the treatment. As for side effects, mild diarrhea developed in only 3 children.

[Clinical evaluation of cefroxadine dry syrup in pediatric field (author's transl)].

Clinical evaluation was carried out on cefroxadine dry syrup (containing 100 mg of cefroxadine per 1 g) for child use, and the following results were obtained. 1. Serum levels: Peak serum levels at 1 hour after single administration of CXD 100 mg (9.1 mg/kg) to a 4-year old child (11kg) and 300 mg (12.8 mg/kg) to a 8-year old child (23.5 kg) were 20.32 microgram/ml and 18.75 microgram/ml, respectively. They declined to 0.78 microgram/ml and 0.88 microgram/ml respectively after 6 hours and to undetectable levels after 8 hours. Half-life was 1 hour and 1.2 hours, respectively. CXD has shown the same concentration pattern as CEX, except for the fact that serum levels were peaked after 30 minutes and not detectable after 6 hours. 2. Clinical responses: CXD was administered, for 7 days, to 33 children with scarlet fever in the dosage of greater than or equal 20 approximately less than 60 mg/kg/day (7 children in greater than or equal to 20 approximately 30 mg/kg/day, 21 in greater than or equal to 30 approximately less than 40 mg/kg/day and 5 in greater than or equal to 40 approximately less than 60 mg/kg/day). Clinical responses were excellent in 19 cases and good in 14 cases, with an efficacy rate of 100%. All strains of group A Streptococcus isolated from the pharynx of 22 children were eradicated within 24 hours. In 1 case each of acute pharyngitis, acute tonsillitis, acute laryngotracheitis and staphylococcal scalded skin syndrome, the dosage of greater than or equal to 30 approximately less than 45 mg/kg/day produced a 100% good clinical response and eliminated the causative pathogens. 3. Side effect: Only 2 cases of eosinophilia were observed in hematologic study as well as in hepatic and renal function tests before and after administration.

[Clinical evaluation of cefroxadine dry syrup in children (author's transl)].

Clinical efficacy of cefroxadine dry syrup, a new oral cephalosporin antibiotic, was evaluated in children, and the following results were obtained. 1. Three children were given a single oral dose of about 10 mg/kg of the drug when fasting, and its blood concentrations were determined. Blood concentrations were maximum at 30 approximately 60 minutes, i.e., 16.9 approximately 18.2 microgram/ml, and markedly low at 4 hours. 2. Thirty-six patients with the following diseases were tested with 23.1 approximately 44.4 mg/kg/day of the drug in 3 to 4 divided doses; 21 patients with lacunar tonsillitis, 2 with tonsillitis, 1 with scarlet fever, 4 with bronchitis and tonsillitis, 2 with cystitis, 4 with pyelonephritis, 1 with impetigo and 1 with probable Mycoplasma pneumonia. An overall efficacy rate in 35 patients excluding the last mentioned case was 91.4%, i.e., excellent in 20, good in 12 and poor in 3, and an eradication rate of the causative organisms was 88.9%. 3. Adverse reactions noted were diarrhea in 1 patient, eruption and diarrhea in 1 transient neutropenia in 1, eosinophilia in 3 and an elevation of GOT and GPT in 1. None were significant. 4. Taste and flavor of the drug was considered to be well palatable to children. 5. Taking into consideration of the results of fundamental evaluation of the drug, cefroxadine dry syrup is considered to be a potent new antibiotic in children, and the recommended dose will be 10 mg/kg 3 to 4 times a day.

[Clinical experience with cefroxadine in bacterial infection of children (author's transl)].

In order to evaluate effectiveness of cefroxadine (CXD) in the treatment of bacterial infections of children, the clinical studies were carried out. CXD was orally administered to 30 patients at daily dose of 27.5 approximately 50.0 mg/kg (average 32.3 mg/kg) in 3 approximately 4 divided dose for 3 approximately 10 days (average 4.9 days). The overall efficacy rate in 30 cases was 93.3%, i.e., excellent 22 (73.3%), good in 6 (20.0%), fair in 1 (3.3%) and poor in 1 case (3.3%). Drug eruption and transient eosinophilia were observed in 1 case each out of 30 cases (6.7%), but any other abnormality was not observed throughout this series. Based on the above results, CXD was thus considered to be a useful antibiotic in treatment of pediatric infections.