Safety, tolerance, and pharmacokinetics of cefepime administered intramuscularly to healthy subjects

Steady state pharmacokinetics, absolute bioavailability, and dose proportionality of cefepime were evaluated in healthy male subjects after single (250, 500, 1000, or 2000 mg) and multiple (1000 mg every 12 hours for 10 days) intramuscular injections. Safety and tolerance were also monitored. High performance liquid chromatography/UV methodology was used to determine cefepime concentrations in plasma and urine. Key pharmacokinetic parameters were determined using noncompartmental methods. Cefepime was absorbed rapidly; mean peak times were 1.0-1.6 hours. Pharmacokinetics were linear over the 250-mg to 2000-mg dose range, with mean total body clearance ranging from 125 to 141 mL/min. The peak plasma concentration and area under the curve increased in a dose-proportional manner. The apparent elimination half-life (2 hours) did not appear to be influenced by dose or by duration of dosing. No accumulation of cefepime was observed during the multiple-dose study. More than 80% of the administered dose was excreted in the urine as unchanged cefepime, and absolute bioavailability after intramuscular dose was 100%. Cefepime was well tolerated. Most subjects experienced none to mild pain and only minimum discomfort at the site of injection.     

Phase I study of ceftizoxime, a new cephalosporin. Single-dose study

A phase I study of ceftizoxime, a new cephalosporin, was performed in 29 subjects. No abnormalities were observed in subjective symptoms, laboratory test results, or physical test results at estimated therapeutic doses of 500 mg intramuscularly, 500 and 1000 mg intravenously, and 2000 mg drip infusion. It is concluded, therefore, that the drug is safe for clinical use. The mean peak serum concentration was dose dependent. The mean serum concentrations of ceftizoxime in man at 5 minutes after 500 and 1000 mg by intravenous bolus were 58.4 and 112.8 micrograms/ml, respectively, which exceed the MIC80 against most pathogens tested. Thus, 500 or 1000 mg was estimated to be the therapeutic dose. The distribution volume of ceftizoxime was 16.0 to 18.6 liters, the total clearance was 135.6 to 154.9 ml/min, and the half-life in the beta-phase was 1.36 to 1.39 hours. Ceftizoxime is mainly excreted in the urine as unchanged drug, at an excretion rate in the 24-hour urine of approximately 80 per cent.     

Fundamental and clinical evaluation of imipenem/cilastatin sodium in the field of pediatrics

A combination drug of imipenem (MK-0787), a new carbapenem antibiotic, and cilastatin sodium (MK-0791) at a ratio of 1:1 was used to treat infections in 8 children, and the concentrations of MK-0787 were determined in plasma, urine and pus of 1 patient and in cerebrospinal fluid of another patient. Eight patients, aged 2 months to 12 years (males: 3, females: 5), were treated with MK-0787/MK-0791. They consisted of 3 with urinary tract infections (causative organisms: E. coli, K. oxytoca plus E. faecalis, and unknown), and 1 patient each with pneumonia (H. influenzae), enteritis (Salmonella C1), cellulitis (S. aureus), purulent lymphadenitis (unknown) and purulent meningitis (E. coli). The dose, ranging from 7.4 mg/7.4 mg/kg to 11.8 mg/11.8 mg/kg, 3 or 4 times daily, was administered by a 30-minute or 60-minute intravenous drip infusion for 5 to 11 days. To the patient with purulent meningitis, however, 25.85 mg/25.85 mg/kg on the 1st day and 12.9 mg/12.9 mg/kg from the 2nd day were administered 4 times daily. Clinical responses in urinary tract infections were excellent in 2 and good in 1, and responses in pneumonia, enteritis, cellulitis, purulent lymphadenitis and purulent meningitis were excellent, good, good, excellent and poor, respectively. The efficacy rate in a total of 8 patients was 87.5%. As adverse reactions, a rash was observed in one patient and a convulsion in another. The rash disappeared after discontinuation of the administration of the drug and the convulsion stopped after a reduction of the dosage. As abnormal laboratory findings, slight prolongation of the prothrombin time was observed in 1 patient, but no bleeding tendency was noted. When MK-0787/MK-0791 (500 mg/500 mg, or 8.7 mg/8.7 mg/kg) was given by a 60-minute intravenous drip infusion to a 12-year-old boy with cellulitis, the peak plasma concentration of MK-0787 was 31.4 micrograms/ml occurring at the end of the infusion, and then the concentration decreased to 13.9 micrograms/ml in 0.5 hour, 8.9 micrograms/ml in 1 hour, 2.8 micrograms/ml in 2 hours, 0.63 microgram/ml in 4 hours and 0.14 microgram/ml in 6 hours. The half-life was 0.83 hour. These plasma levels provided concentrations exceeding MIC90's against major infective bacteria for 2 hours. The urinary recovery in the first 7 hours was 75.0%, and the urinary concentration was greater than 100 micrograms/ml for 5 to 7 hours.(ABSTRACT TRUNCATED AT 400 WORDS)     

Multiple-dose pharmacokinetics, safety, and tolerability of bosentan, an endothelin receptor antagonist, in healthy male volunteers.

The multiple-dose pharmacokinetics, safety, and tolerability of oral bosentan, a selective endothelin receptor antagonist, were investigated in healthy male volunteers. In study A, an ascending-dose, double-blind, placebo-controlled trial, doses of 100, 200, 500, and 1000 mg bosentan or placebo were given once daily for 8 days as tablets (100 and 500 mg dose strength). In study B, a double-blind, placebo-controlled trial, 500 mg tablets of bosentan or placebo tablets were given once daily for 8 days with two additional single intravenous dose administrations of 250 mg bosentan 48 hours before the first and 24 hours after the last oral dose. The drug was very well tolerated. No effects on pulse rate, ECGs, or clinical laboratory tests were observed. Marginal effects on blood pressure were seen in subjects only when standing. The oral bioavailability of bosentan was 43% to 48%, with a small interindividual variability of 20%. Doses above 500 mg did not lead to significant further increases in plasma levels of bosentan. From the first to the last day of the oral treatment phase, plasma concentrations of bosentan decreased by 30% to 40% due to a 2-fold increase in plasma clearance. Absorption and plasma protein binding did not change. The 24-hour urinary excretion of 6 beta-hydroxycortisol was increased in parallel by approximately 1.7-fold, indicating induction of cytochrome P450 3A isozymes. The two metabolites of bosentan reached plasma concentrations well below those of bosentan and will most likely not contribute to the pharmacological activity.     

Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem

Prolonging the infusion of meropenem over 3 hours increases the percentage of the dosing interval that drug concentrations remain above the minimum inhibitory concentration (MIC), thereby maximizing the pharmacodynamics of this agent and adhering to drug stability constraints. Monte Carlo simulation was employed to determine pharmacodynamic target attainment rates for several prolonged infusion (PI) meropenem dosage regimens as compared with the traditional 30-minute infusion (TI) against Enterobacteriaceae, Acinetobacter species, and Pseudomonas aeruginosa populations. Percent time above the MIC (%T>MIC) exposures for 1000 mg TI q8h, 2000 mg TI q8h, 500 mg PI q8h, 1000 mg PI q12h, 1000 mg PI q8h, 2000 mg PI q12h, and 2000 mg PI q8h were simulated for 10,000 subjects. Variability in pharmacokinetic parameters and MIC distributions were derived from studies in healthy volunteers and the MYSTIC surveillance program, respectively. The probabilities of attaining bacteriostatic (30% T>MIC) and bactericidal (50% T>MIC) exposures were high for all dosage regimens against populations of Enterobacteriaceae. Against Acinetobacter species and Pseudomonas aeruginosa, the 2000-mg PI q8h dosage regimen provided the highest target attainment rates. For mild to moderate infections caused by Enterobacteriaceae, prolonged infusion regimens of 500 mg PI q8h and 1000 mg PI q12h would provide equivalent target attainment rates to the traditional 30-minute infusion while requiring less drug over 24 hours. For more serious infections presumably caused by Acinetobacter species or Pseudomonas aeruginosa, a dose of 2000 mg PI q8h is recommended because of its high bactericidal target attainment rate against these pathogens. Further study of these dosage recommendations in clinical trials is suggested.     

Studies of rokitamycin in pediatrics

Pharmacokinetic, bacteriological and clinical studies on a new macrolide antibiotic, rokitamycin (RKM) dry syrup for pediatric use, were done, and results as summarized below were observed: 1. Five children with ages between 6 and 10 years were administered orally with RKM at a dose level of 10 mg/kg either at 30 minutes before or 30 minutes after meal on a crossover design, and plasma concentrations and urinary excretion rates of the drug were measured. Plasma concentrations of RKM following the administration before meal were 0.50 microgram/ml at 1/2 hour, 0.43 microgram/ml at 1 hour, 0.15 microgram/ml at 2 hours, 0.03 microgram/ml at 4 hours, and not detectable at 6 hours. Plasma concentrations following the administration after meal were 0.11 microgram/ml at 1/2 hour, 0.15 microgram/ml at 1 hour, 0.09 microgram/ml at 2 hours, 0.03 microgram/ml at 4 hours, and not detectable at 6 hours. The 0-6 hour urinary recovery rates were 1.41% following the administration before meal, and 0.93% following the administration after meal. These results suggested that the drug might be absorbed more rapidly, giving a higher plasma concentration, when administered before meal than when administered after meal. Changes in plasma concentrations of RKM following the administration of 10 mg/kg before meal were similar to those of two 100 mg RKM tablets (TMS-19-Q.GC tablets) to adult patients. Therefore, it seemed optimal to administer 10 mg/kg 3 times daily at fasting to children as a rule.(ABSTRACT TRUNCATED AT 250 WORDS)     

Basic studies of cefotiam (author's transl)

The basic studies of cefotiam (CTM) were performed, and the following results were obtained. 1. One shot intravenous injection of 40 mg/kg of CTM (1) Serum levels: The mean levels of CTM in 3 children were 133.9 micrograms/ml after 15 minutes, 71.5 micrograms/ml after 30 minutes 32.6 micrograms/ml after 1 hour, 9.2 micrograms/ml after 2 hours, 2.5 micrograms/ml after 4 hours, 0.9 microgram/ml after 6 hours. The serum half life of CTM was approximately 1.2 hours on beta-phase. (2) Urinary excretion: The mean urinary excretions were 39.4% over 3 hours, 44.7% over 4 hours, 45.7% over 6 hours. 2. 1 hour-drip infusion of 40 mg/kg of CTM (1) Serum levels: The mean serum levels of CTM in 4 children were 140.1 micrograms/ml at immediately after drip infusion was completed, 10.6 micrograms/ml after 1 hour, 3.8 micrograms/ml after 2 hours, 1.4 micrograms/ml after 3 hours, 0.5 microgram/ml after 5 hours. The serum half life of CTM was approximately 1.0 hour on beta-phase. (2) Urinary excretions: The mean urinary excretions were 42.9% over 2 hours, 48.0% over 4 hours, 48.7% over 6 hours. 3. Bioactive metabolite in serum and urine: No bioactive metabolites were observed in either serum or urine after administration of 40 mg/kg of CTM.     

Fundamental and clinical studies in pediatric field on ceftizoxime (author's transl)

Fundamental and clinical studies in the pediatric field on ceftizoxime were carried out, and the following results were obtained. 1. In 4 children age from 3 years to 5 years, the serum concentrations and urinary excretion of ceftizoxime in a dose of 20 mg/kg by intravenous drip infusion over 60 minutes were measured. The peak serum levels were 22.0--84.0 microgram/ml (mean 45.0 microgram/ml) at the end of infusion. The mean serum levels after the end of infusion were 16.9 microgram/ml at 30 minutes, 12.1 microgram/ml at 1 hour, 6.2 microgram/ml at 2 hours, 1.6 microgram/ml at 4 hours and 0.6 microgram/ml at 6 hours, with mean serum half-life (T 1/2) of 1.03 hours, mean urinary recovery rate was 64.9% up to 6 hours. 2. Concentrations of the drug in the cerebrospinal fluid in 1 patient with purulent meningitis at 30 minutes after an intravenous drip infusion of about 33.3 mg/kg were 0.2 to 1.5 microgram/ml, which were 8 to 60 times higher than the MICs of the causative organisms. 3. Ceftizoxime was administered to 38 children with pneumonia, bronchitis, Salmonella enteritis, purulent meningitis, etc. in the daily dose of 44--200 mg/kg for 3--19 days. Clinical response was excellent in 24, good in 12, poor in 1 and unknown in 1. The drug was proved to be very effective in 1 case of purulent meningitis due to H. influenzae. As for side effect, eruption was observed in only 1 case.     

Pharmacokinetic studies of astromicin using a constant-rate continuous intravenous infusion method

Astromicin (ASTM) was administered intravenously to 4 healthy adult volunteers with an average body weight of 62 kg using a continuous infusion apparatus at a constant rate of 200 mg in 1 hour (Group I), 400 mg in 1 hour (Group II) and 200 mg in 2 hours (Group III). Concentrations of the drug in serum and urine were determined by high power liquid chromatography (HPLC). The mean serum concentration of the 4 subjects reached the peak of 13.32 micrograms/ml in Group I, 22.12 micrograms/ml in Group II and 9.89 micrograms/ml in Group III. The peak concentration was achieved at the end of infusion and was dose-related. After 8 hours, the concentration dropped to less than 1 micrograms/ml in all groups. The urinary recovery rate was 90% in 8 hours and 95% in 24 hours. T1/2 (beta) analyzed by the two-compartment open model was 1.64-1.72 hours. AUC infinity was also dose-related, such as 33.1 micrograms X hr/ml and 31.6 micrograms X hr/ml in Group I and Group III, and 57.6 micrograms X hr/ml in Group II. It is recommended for amikacin (AMK) that the peak serum concentration should not exceed 35 micrograms/ml and the maximum concentration before the next infusion should be less than 5 micrograms/ml. In these experiment, ASTM which is lower in toxicity than AMK did not approach 35 micrograms/ml even at the peak level with the dosage of 400 mg in 1 hour. Furthermore, the excretion of the drug was fast and the serum level of the drug became much lower than 5 micrograms/ml very quickly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Safety, tolerability, and single- and multiple-dose pharmacokinetics of piperaquine phosphate in healthy subjects

Piperaquine phosphate is an orally active bisquinolone antimalarial drug that has been used for the past 3 decades. The authors report the safety, tolerability, and pharmacokinetics of piperaquine from a classical controlled phase I study. It was a double-blind, randomized, parallel-group, placebo-controlled, and single- and multiple-dose study. During the rising single-dose study, single ascending oral doses of 500, 750, 1000, 1250, and 1500 mg of piperaquine phosphate were administered, whereas in rising multiple-dose study, once-daily ascending oral doses of 500, 750, 1000, and 1500 mg were administered for 3 consecutive days. Pharmacokinetic analysis for both the rising single- and multiple-dose studies was done using the noncompartmental approach. The mean apparent terminal half-life ranged from 11 to 23 days. Increase in exposure was less than dose proportional and linear. Piperaquine concentrations were measurable up to 60 days postdose. Multiple peaks were observed in the plasma piperaquine concentration-time profiles and exhibited 3- to 7-fold accumulation following multiple dosing. Piperaquine was well tolerated following single and multiple doses.     

Clinical study on imipenem/cilastatin sodium in the field of pediatrics

Imipenem/cilastatin sodium (MK-0787/MK-0791) was administered to pediatric patients with infections, and the following results were obtained. Pharmacokinetic study Two children, 11 years of age (38 kg body weight) and 3 years of age (15.5 kg body weight), were administered by 30 minutes intravenous drip infusion a single dose of 500 mg/500 mg (13.2 mg/13.2 mg per kg) and 250 mg/250 mg (16.1 mg/16.1 mg per kg) of MK-0787/MK-0791, respectively. Serum concentrations of MK-0787 reached their peaks at the end of drip infusion at a value of 56.33 micrograms/ml and 55.98 micrograms/ml, respectively. Concentrations of the drug decreased as the time after the administration increased, and they reached 0.14 microgram/ml and 0.12 microgram/ml, respectively in the older and the younger children at 6 hours after the administration. Half-lives (T 1/2) of the drug in serum were calculated to be 1.21 hours and 1.04 hours, respectively. The concentration of the drug in cerebrospinal fluid for the 11 years old was 0.52 microgram/ml 2 hours after the drip infusion and the serum concentration at the time was 4.02 micrograms/ml. Peak serum concentrations of MK-0791 in the 2 children were 53.73 micrograms/ml and 22.99 micrograms/ml, respectively, at the end of drip infusion. After 1 hour, the serum concentration of the drug decreased to 10.54 micrograms/ml in 1 case and not detectable in the other case. Urinary recovery rates of MK-0787 in 6 hours after the drip infusion was 82.9% and 63.6% in the 2 children and those of MK-0791 were 57.9% and 74.6%. Clinical study Clinical studies on MK-0787/MK-0791 were carried out in 6 pediatric patients; 1 each with femoral cellulitis, sepsis suspected, salmonellosis, acute tonsillitis, bronchopneumonia and streptococcosis. Lengths of treatment were 2 2/3-4 days for 5 cases and 6 days for 1 case. The patients were treated by 30-60 minutes intravenous drip infusions twice a day for 1 case, and 3 times a day for 5 cases at daily doses of 54.5-66.7 mg/kg. The treatment was effective in all cases, with 3 cases judged excellent and 3 cases good. The safety of the drug was studied in 7 patients. No side effects nor clinically abnormal values were observed in any cases.     

Studies on panipenem/betamipron in the field of pediatrics]

Pharmacokinetic and clinical studies in pediatrics were performed on panipenem/betamipron (PAPM/BP), a combined drug of a carbapenem antibiotic (panipenem) and organic ion inhibitor (betamipron) at a weight ratio of 1:1. 1. Plasma levels and urinary excretion were studied when PAPM/BP, at 10 mg/10 mg/kg (4 cases) or 20 mg/20 mg/kg (5 cases), was administered using intravenous drip infusion in 30 minutes to 9 children (4-14 years old). The plasma PAPM level at the end of drip infusion was 30.75 +/- 4.98 micrograms/ml in the cases administered with 10 mg/10 mg/kg and 68.72 +/- 5.73 micrograms/ml in the cases administered with 20 mg/20 mg/kg. Drug concentrations then gradually decreased with half-lives of 1.08 +/- 0.09 hours and 0.98 +/- 0.02 hour, and reached 0.39 +/- 0.14 micrograms/ml and 0.62 +/- 0.06 micrograms/ml, respectively, after 5.5 hours. Plasma BP levels at the end of drip infusion was 18.93 +/- 3.75 micrograms/ml in the cases administered 10 mg/10 mg/kg and 37.09 +/- 2.68 micrograms/ml in the cases administered 20 mg/kg, and half-lives were 0.55 +/- 0.07 hour and 0.61 +/- 0.03 hour, respectively; the plasma BP level could not be determined in any cases after 5.5 hours. Mean urinary recovery rates of PAPM in the first 6 hours after the start of intravenous drip infusion were 33.0 +/- 6.1% in the cases administered 10 mg/10 mg/kg and 21.8 +/- 2.3% in the cases administered 20 mg/20 mg/kg and those of BP were 77.0 +/- 2.4% and 76.6 +/- 7.3%, respectively. 2. When PAPM/BP, was administered at 31.3 mg/31.3 mg/kg thought by intravenous drip infusion in 30 minutes to 1 case of purulent meningitis, PAPM levels were 0.76 micrograms/ml at the end of drip infusion but varied between 0.80 to 1.97 micrograms/ml 30 minutes after the end of drip infusion during 8 days of treatment. 3. PAPM/BP was administered to 43 cases, 47 diseases of bacterial infections in the domain of pediatrics to study its clinical efficacy, bacteriological efficacy and adverse reactions. Single doses were 5.2mg/5.2mg to 31.3 mg/31.3 mg/kg; frequencies of administration were 3 to 4 times a day, and durations of administration were 3 1/3 to 11 days; and total dosages ranged between 1.125 g/1.125 g and 11.0 g/11.0 g.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetic and clinical evaluations of micronomicin by intravenous drip infusion

The safety and pharmacokinetics of micronomicin (MCR) by intravenous drip infusion were evaluated and the intravenous drip infusion of MCR was carried out on several cases on which the blood levels and clinical usefulness of MCR were investigated. Five healthy adult male volunteers received by crossover method 1 hour intravenous drip infusion of MCR in doses of 60 and 120 mg and intramuscular injection in a dose of 120 mg. The mean highest serum level was 6.3 micrograms/ml by intravenous drip infusion of 60 mg, 10.7 micrograms/ml by intravenous drip infusion of 120 mg, and 10.3 micrograms/ml by intramuscular injection of 120 mg. Serum levels of MCR were similar for intravenous drip infusion and intramuscular injection of 120 mg of MCR. The biological serum half-lives of MCR were 2.15 hours by 1 hour intravenous drip infusion of 60 mg, 2.54 hours by 1 hour intravenous drip infusion of 120 mg, and 1.59 hours by intramuscular injection of 120 mg. The mean urinary recovery rates within 24 hours after administration were 74.3% by 1 hour intravenous drip infusion of 60 mg, 59.6% by 1 hour intravenous drip infusion of 120 mg, and 64.9% by intramuscular injection of 120 mg, the results being nearly consistent. In all treatment groups, MCR could be safely administered. Intravenous drip infusion of MCR in a dose of 60 or 120 mg once or twice a day was conducted on a total of 6 cases consisting of 2 cases of pneumonia and 4 cases of urinary tract infections.(ABSTRACT TRUNCATED AT 250 WORDS)     

Basic and clinical studies of cefotiam in pediatric field (author's transl)

The basic and clinical studies of cefotiam (CTM) in pediatric infections were carried out, and the following results were obtained: 1. The antibacterial activity of CTM against S. aureus was equal or slightly less than that of cefazolin (CEZ). Those of CTM against E. coli and K. pneumoniae were eight times more active than those of CEZ. 2. CTM 20 mg/kg was administered wither by 30 minutes or 1 hour intravenous drip infusion. The peak serum levels were obtained at the end of each drip infusion, with the mean peak levels being 44.8 and 41.4 mcg/ml respectively. The serum levels at 1.5 and 2 hours after drip infusion were 2.8 and 2.2 mcg/ml respectively, and at 3.5 and 4 hours after drip and 4 hours after drip infusion were 0.3 and 0.7 mcg/ml respectively. The half lives were 0.62 and 1.15 hours, respectively. The mean urinary excretion over 6 hours were 52.8% in ;the 30 minutes drip infusion group and 42.6% in the 1 hour drip infusion group. 3. Clinical efficacy was evaluated in sixteen cases suffering from tonsillitis (4 cases), pneumonia (4), bronchitis (2), cervical lymphadenitis (2), purulent meningitis (2), suppurative arthritis (1) and suspected sepsis (1). Good and excellent responses were obtained in 15 of 16 cases (93.8%). Bacteriological response in the form of eradication was noted in 4 of 6 cases. Side effect observed was rash in 1 case, and laboratory abnormalities were elevation of BUN in 1 case and elevation of GPT in 2 cases.     

Pharmacokinetics and pharmacodynamics of pentopril, a new angiotensin-converting-enzyme inhibitor in humans

In a single, ascending-dose tolerance study, nine healthy volunteers were given oral pentopril 50 to 750 mg (CGS 13945) in groups of three each. Disposition characteristics of pentopril and its active metabolite (CGS 13934) were determined using plasma concentration and urinary excretion data. The drug was absorbed rapidly following zero-order kinetics. The drug has an apparent volume of distribution of 0.83 L/kg and an oral clearance of about 0.79 L/hr/kg. Urinary excretions, calculated after 125- and 250-mg doses, showed a dose proportional urinary recovery of 21% (+/- 5%) for pentopril and 40% (+/- 5%) for CGS 13934. In the multiple-dose study of 125 mg orally q12h in six healthy subjects, the plasma concentrations for both drug and metabolite showed no appreciable accumulation of either compound, which was expected from their short pharmacokinetic half-lives (pentopril, less than 1 hr; CGS 13934, approximately 2 hr). In a separate pharmacodynamic study, drug and metabolite concentrations were evaluated against angiotensin-I (AI)-induced changes in blood pressure and plasma angiotensin-converting-enzyme (ACE) activity in healthy volunteers after single oral doses (range, 10-500 mg). The pharmacodynamic half-life for plasma ACE inhibition increased with the dose (10 mg, 1.5 hr; 500 mg, 9.8 hr). There was a close relationship between the plasma level of the metabolite and the inhibition of plasma ACE activity and AI-induced pressor response. A hyperbolic function adequately described the dependence of plasma ACE activity on plasma metabolite concentration with a concentration at half-maximal inhibition of 53 ng/mL.     

Pharmacokinetic and clinical studies on sulbactam/ampicillin in the pediatric field

Pharmacokinetic and clinical studies of sulbactam/ampicillin (SBT/ABPC) were conducted and the obtained results are summarized as follows. For pharmacokinetic investigation, SBT/ABPC at 30 or 60 mg/kg was administered by intravenous drip infusion over 30 minutes. The maximum blood concentration was reached just after the completion of the drip infusion in both groups. The mean peak serum concentrations of SBT and ABPC were 22.4 +/- 0.8 micrograms/ml and 32.8 +/- 1.0 micrograms/ml, respectively, in the 30 mg/kg group, and they were 54.2 micrograms/ml and 93.8 micrograms/ml, respectively, in the 60 mg/kg group. The concentrations were dose-related. The mean half-lives of SBT and ABPC following 30 mg/kg SBT/ABPC administration were 0.91 +/- 0.04 hour and 0.90 +/- 0.05 hour, respectively, and those following 60 mg/kg SBT/ABPC were 1.08 hours and 0.84 hour, respectively. The highest urinary concentration occurred 0-2 hours after the 30 minutes drip infusion. Mean urinary excretion rate of SBT and ABPC over 6 hours were 71.4 +/- 2.5% and 54.6 +/- 3.3%, respectively, in the 30 mg/kg group, and they were 80.0% and 63.7%, respectively, in the 60 mg/kg group. In the clinical investigation conducted with a total of 24 patients (15 with respiratory tract infections, 3 with urinary tract infections, 2 with lymphadenitis, and others), SBT/ABPC was found to be excellent in 14 cases, good in 9, fair in 1. The efficacy rate was, therefore, 95.8%. In the bacteriological evaluation, 9 out of 11 clinically isolated strains were eradicated, 1 unchanged and 1 unknown. The elimination rate was 90.0%. Regarding side effects, no abnormal clinical symptoms were observed. As abnormal laboratory values, a slight elevation of GOT was observed.     

Steady-state pharmacokinetics of a novel extended-release metformin formulation

BACKGROUND AND OBJECTIVE: Metformin is an effective treatment for type 2 diabetes mellitus. The pharmacokinetic characteristics of the conventional immediate-release (IR) formulation of metformin (Glucophage), however, necessitate two- or three-times-daily dosing. Development of a novel extended-release (XR) formulation of metformin (Glucophage XR) using GelShield Diffusion System technology provides a once-daily dosing option. The objective of this study was to assess the steady-state pharmacokinetics of metformin XR tablets. STUDY DESIGN: This was an open-label, multiple-dose, five-regimen, two-sequence clinical study lasting 5 weeks. METHODS: Subjects were 16 healthy volunteers aged 18-40 years. Three 1-week regimens of metformin XR (500, 1000 and 1500 mg once daily) were administered sequentially. Subjects were alternately given either metformin XR 2000 mg once daily or metformin IR 1000 mg twice daily during weeks 4 and 5. The pharmacokinetic properties of metformin XR were assessed on two separate days at steady state and compared with those of metformin IR. RESULTS: Absorption of metformin XR was slower than that of metformin IR (time to maximum plasma concentration = 7 versus 3 hours). Maximum plasma concentrations (Cmax) following the administration of metformin XR 2000 mg once daily was 36% higher than that following the evening dose of metformin IR 1000 mg twice daily. The extent of absorption, determined by area under the plasma concentration-time curve (AUC), was equivalent for both formulations. The mean accumulation ratio of metformin XR was 1.0, indicating no accumulation with multiple-dose administration. Intrasubject variabilities in Cmax and AUC of metformin were comparable between metformin XR and metformin IR. This novel formulation of metformin XR was well tolerated at single doses up to 2000 mg once daily for 7 days, and adverse events were similar to those reported with metformin IR. CONCLUSION: The pharmacokinetic parameters of metformin XR tablet using GelShield Diffusion System technology were similar to those of metformin IR. Metformin XR was well tolerated at single doses up to 2000 mg once daily.     

Fundamental and clinical studies of imipenem and imipenem/cilastatin sodium in the field of obstetrics and gynecology

Fundamental and clinical studies of imipenem (MK-0787), a new type of carbapenem antibiotic, and MK-0787 combined with cilastatin sodium (MK-0791), a renal dipeptidase inhibitor, were carried out. The results obtained were as follows: MK-0787 500 mg alone or MK-0787 500 mg with MK-0791 500 mg was administered by intravenous drip infusion over 30 minutes. Plasma levels of the drug were similar either following the administration of 500 mg of MK-0787 alone or 500 mg of MK-0787 with 500 mg of MK-0791. When MK-0787 was administered with MK-0791, MK-0787 and MK-0791 levels at 2 hours after the end of infusion in uterine arterial plasma were 6.8 micrograms/ml and 3.2 micrograms/ml, respectively, and in venous plasma were 8.4 micrograms/ml and 4.7 micrograms/ml, respectively. MK-0787 tissue levels ranged from 0.8 microgram/g to 3.8 micrograms/g at 205 minutes after the end of infusion. Based on these results, the plasma and tissue levels of MK-0787 and MK-0791 with b.i.d. dosage exceeded the MICs of the drug against clinical isolates in the field of obstetrics and gynecology such as E. faecalis, E. coli Klebsiella sp., Peptococcus sp., Peptostreptococcus sp. and B. fragilis immediately after the administration. However, it seemed that the b.i.d. dosage was insufficient to maintain the in vivo concentration of these agents high enough to inhibit the growth of the above bacteria. Eighteen patients with obstetric and gynecologic infection (12 with intrauterine infections, 2 with pelvic dead space inflammation, 2 with pelvic peritonitis, 1 with a vaginal cuff abscess and 1 with a vulvar abscess) and 1 patient with other infection (abdominal wall abscess) were evaluated, but 1 patient with pelvic peritonitis was later excluded from the efficacy evaluation because of a serious illness. MK-0787/MK-0791 was administered twice daily in a 30-minute intravenous drip infusion. Clinical results were excellent in 1 patient, good in 16 and poor in 1, for an efficacy ratio of 94.4%. No side effects were observed. Only abnormal laboratory findings observed were elevation of S-GOT and S-GPT in 1 patient which normalized 2 weeks after the treatment was discontinued. These results suggest that MK-0787/MK-0791 will be useful for the treatment of obstetric and gynecologic infections.     

Pharmacokinetic and pharmacodynamic analysis of a novel leukotriene biosynthesis inhibitor, MK-0591, in healthy volunteers.

1. The pharmacokinetic and pharmacodynamic properties of a novel 2-indolealkanoic acid derivative (MK-0591), a potent inhibitor of leukotriene biosynthesis, were investigated in healthy male Japanese volunteers. Single oral doses of 50, 125, 250 and 500 mg and multiple oral doses of 125 mg twice daily for 9.5 days and 250 mg once daily for 10 days were administered. 2. After the single-dose administration following overnight fasting, Cmax and AUC of MK-0591 in plasma increased in a dose-dependent manner, while elimination half-life remained constant (11.2-13.2 h) irrespective of dose. Food intake decreased Cmax and AUC by 71% and 68%, respectively, at a dose of 250 mg. With respect to multiple-dose administration before meals, there were no significant differences in the pharmacokinetic parameters between the first and last days, indicating a lack of significant accumulation of MK-0591 in plasma. Urinary recovery as the unchanged form was negligible throughout the study. 3. Ionophore-stimulated production of leukotriene B4 (LTB4) in blood ex vivo was inhibited significantly from 1 h until 12 to 48 h after single-dose administration as compared with predose value. In parallel, the urinary excretion of endogenous leukotriene E4 (LTE4) was significantly decreased from 4 to 8 h until 48 to 72 h after drug administration. Reduction of ionophore-stimulated LTB4 biosynthesis and urinary excretion of LTE4 following single administration of MK-0591 was statistically significant as compared with placebo group, and the duration of inhibition of LTB4 biosynthesis was dose-related.(ABSTRACT TRUNCATED AT 250 WORDS)     

Laboratory and clinical studies on ceftizoxime in the field of pediatrics (author's transl)

Ceftizoxime, a new cephalosporin preparation, was evaluated for its antibacterial activity, absorption, excretion and clinical effectiveness, and the following results were obtained. The minimum inhibitory concentrations (MICs) of ceftizoxime against 211 clinical isolates were determined in comparison with those of cefazolin, cefmetazole, cefotiam and 6059 S. Against S. pyogenes (50 strains), ceftizoxime was 1 tube inferior to cefazolin inoculum size of 10(8) cells/ml, but was 2--3 tubes superior to cefmetazole and 6059-S. Against E. coli (50 strains), ceftizoxime and 6059-S were significantly more active than the other drugs. The susceptibility pattern of Klebsiella sp. (50 strains) to ceftizoxime was similar to that to cefotiam and 6059-S. Against Proteus sp. (50 strains), cefotiam and 6059-S were more active than the other drugs. Ceftizoxime was intermediate in activity, and cefazolin was the least active. Against H. influenzae (11 strains), ceftizoxime was the most active, with concentrations of 0.1 mcg/ml required to inhibit 100% of strains with an inoculum size of 10(8) cells/ml and 10(6) cells/ml. A dose of ceftizoxime 10 mg/kg or 20 mg/kg was administered to 15 patients aged from 5 years to 12 years, and serum levels and urinary excretion of the drug were measured. Intravenous bolus injection of the drug in dose of 10 mg/kg and 20 mg/kg yielded mean serum levels of 26.6 mcg/ml and 55.7 mcg/ml at 30 minutes, respectively. The serum levels of the drug, thereafter, declined gradually but still remained 1.3 mcg/ml and 2.7 mcg/ml at 6 hours. The serum half-lives (T 1/2) were estimated to be 1.17 hours in dose of 10 mg/kg and 1.31 hours in dose of 20 mg/kg. When a dose of 20 mg/kg was infused over a period of 30 minutes, the serum levels attained the peak of 72.4 mcg/ml to 82.4 mcg/ml (mean 79.4 mcg/ml) at the end of infusion. The levels, thereafter, tapered to mean levels of 45.3 mcg/ml at 30 minutes, 24.7 mcg/ml at 1 1/2 hours, and 3.6 mcg/ml at 5 1/2 hours, with a T 1/2 of 1.22 hours. Meanwhile, when the same dose was infused over 1 hour, the serum levels attained the peak of 59.4 mcg/ml to 68.5 mcg/ml (mean 64.2 mcg/ml). The mean serum levels after the end of infusion were 41.3 mcg/ml at 30 minutes, 21.6 mcg/ml at 1 hour and 1.9 mcg/ml at 5 hours, with a T 1/2 of 0.97 hours. Urinary recovery of the drug was 69.2% to 79.9% after intravenous injection and 62.3% to 79.9% after drip infusion, most of the given drug was excreted in the first 2 hours after administration. In our clinical study, 27 children with moderate or severe infections (12 cases of bronchopneumonia or bronchitis, 5 of pyelonephritis, 3 of purulent meningitis, etc.) were treated with ceftizoxime at the daily dose of 30--309 mg/kg for 3--23 days. Clinical response was excellent in 10, good in 9, fair in 5 and poor in 3. The drug was proved to be very effective against infections due to H. influenzae K. pneumoniae, E. coli and S. aureus. No serious side effects were observed in any case.