Basic and clinical studies on tazobactam/piperacillin in pediatric field

A drug susceptibility test of the combination drug TAZ/PIPC, which consists of a newly developed beta-lactamase inhibitor, tazobactam (TAZ), and one of penicillin antibiotics, piperacillin (PIPC), with combination ratio of 1:4 in potency, was conducted with stock strains and clinical isolates. The clinical efficacy and safety of its injection was also evaluated in children with a variety of infectious diseases. The results were as follows: 1. In susceptibility test, 114 strains from 4 species of stock strains were treated with 8 drugs, that is, TAZ/PIPC, PIPC, penicillin G (PCG), ampicillin (ABPC), cefotiam (CTM), cefotaxime (CTX), ceftazidime (CAZ), and sulbactam/cefoperazone (SBT/CPZ). Of three clinically isolated species from patients, Staphylococcus aureus (S. aureus) was treated with TAZ/PIPC, PIPC, methicillin (DMPPC), CTM, CTX, and SBT/CPZ, and the others were treated with the same drugs except for DMPPC. The MICs were measured for these bacterial strains inoculated at the concentration of 10(6) CFU/ml. The MIC90 values of TAZ/PIPC against 45 strains of Streptococcus pyogenes (S. pyogenes), one of the stock cultures of Gram-positive cocci, were 0.05 microgram/ml and similar to those of PIPC, CTM, CAZ, and SBT/CPZ. The MICs of TAZ/PIPC for 28 strains of Streptococcus agalactiae (S. agalactiae) were 0.39 microgram/ml and similar to those of PIPC, CTM, CAZ, and SBT/CPZ. As for Gram-negative bacilli, the MIC90 of TAZ/PIPC against 10 strains of Bordetella pertussis (B. pertussis) were 0.10 microgram/ml and similar to those of PIPC. The MIC90 of TAZ/PIPC against 31 strains of Haemophilus influenzae (H. influenzae) were 0.05 microgram/ml and similar to those of PIPC, CTX, and SBT/CPZ. Regarding Gram-positive cocci isolated from patients received this combination drug, the MIC90 of TAZ/PIPC against 2 strains of S. aureus, a non beta-lactamase producing strain and a low-beta-lactamase producing strain, were 0.78 microgram/ml and 3.1 micrograms/ml, respectively; the former value was similar to those of PIPC, DMPPC, CTM, and CTX, and the latter was similar to those of PIPC, DMPPC, CTX, and SBT/CPZ. Of 4 strains of Streptococcus pneumoniae, 2 strains were inhibited at 0.05 microgram/ml, and the others at 1.56 micrograms/ml; both values were similar to those of PIPC, SBT/CPZ. As for Gram-negative bacilli, 6 of 7 strains of H. influenzae did not produce beta-lactamase and 1 strain was a high producer. The MICs of TAZ/PIPC against beta-lactamase nonproducing strains were < or = 0.025 microgram/ml in 5 strains and 0.39 microgram/ml in 1 strain, and the values were similar to those of PIPC and SBT/CPZ. While the MIC of TAZ/PIPC against the high beta-lactamase producing strain was 0.78 microgram/ml; similar to that of SBT/CPZ and smaller than that of PIPC. 2. The results of clinical effects on 7 diseases in 33 cases were as follows: TAZ/PIPC was clinically judged "excellent" in 17 (51.5%); good in 14 (42.4%); fair in 2 (6.1%). No case with no response was seen in this study, and the total efficacy rate of "excellent" and "good" was 93.9%. 3. Bacteriological effects were evaluated in 17 strains of 4 species, and all of them were eradicated. 4. Adverse reactions were judged in 35, which consisted of 33 in which the clinical effects were evaluated and 2 dropped from this study. Of these cases, diarrhea was observed in 4 (11.4%). 5. Laboratory tests revealed an increase in platelets in 1 of 32 cases (3.1%), and eosinophilia in 2 of 29 cases (6.9%). Biochemical profile showed an increase in GPT alone and abnormal increases in both GOT and GPT in 1 each out of 21 cases.     

Pharmacokinetic, bacteriological and clinical evaluation of tazobactam/piperacillin in pediatrics

Pharmacokinetic, bacteriological and clinical studies were performed in pediatrics on tazobactam/piperacillin (TAZ/PIPC), a combined drug of a new beta-lactamase inhibitor tazobactam and piperacillin at a ratio of 1:4. 1. Serum levels and urinary excretions of TAZ, PIPC and desethyl piperacillin (DEt-PIPC), a metabolite of PIPC, after one shot intravenous administration of 50 mg/kg of TAZ/PIPC to two children (6-7 years old) were investigated. The serum TAZ level at 0.08 hour was 50.8-51.0 micrograms/ml after administration. Then TAZ concentrations gradually decreased with half-lives of 0.38-0.45 hour, and reached 1.0-1.4 micrograms/ml after 2 hours and was not detected after 3 hours and 6 hours. Serum PIPC levels at 0.08 hour was 167.0-231.0 micrograms/ml after administration. Then PIPC concentrations gradually decreased with half-lives of 0.41-0.55 hour, and reached 1.2-2.4 micrograms/ml after 3 hours and was not detected after 6 hours. DEt-PIPC was detected slightly in serum. A ratio of TAZ to PIPC was about 1 to 4 in serum at each time. Urinary recovery rates of TAZ in the first 6 hours after administration of TAZ/PIPC were 33.5-90.1% and those of PIPC were 41.9-77.8% and those of DEt-PIPC were 1.5-2.8%. 2. TAZ/PIPC was administered to 27 pediatric patients (their ages ranged between 2 months and 11 years old) with various infections, and clinical and bacteriological effects and adverse reactions were investigated. Single doses were 26.2-55.6 mg/kg, frequencies of administration were 3-4 times a day, and durations of administration were 3 1/3-7 1/3 days, and total dosages were 4.5-33.75 g. Clinical effects were evaluable in 26 cases. Responses were rated as "good" in acute purulent tonsillitis 1 case and acute purulent otitis media 1 case, as "excellent" in acute sinusitis 1 case, as "excellent" in 2 and "good" in 1 out of 3 cases of acute bronchitis, as "excellent" in 13 and "good" 2 out of 15 cases of acute pneumonia, as "excellent" in acute urinary tract infection 2 cases and as "excellent" in acute enteritis in 1 case, acute appendicitis in 1 case and lymphadentis in 1 case. In all cases, the results were rated as "good" or "excellent". Antimicrobial effects against a total of 10 strains identified or assumed to be pathogenic bacteria were evaluated. The 10 strains of bacteria included 4 strains of Streptococcus pneumoniae, 3 strains of Haemophilus influenzae (2 strains beta-lactamase producing), 2 strains of beta-lactamase producing Moraxella catarrhalis, 1 strain of beta-lactamase producing Morganella morganii. All the bacteria listed here were judged to have been eradicated. Adverse reaction was observed in 1 case with mild diarrhea. As abnormal changes in laboratory data, leucocytopenia in 1 case, elevation of GOT. GPT in 2 cases and eosinophilia in 1 case were observed. On the basis of the findings, TAZ/PIPC was considered to be effective and safe in the treatment of pediatric infections.     

Fundamental and clinical studies on tazobactam/piperacillin in the pediatric field

The incidence of hip fractures worldwide is expected to almost quadruple in the next 60 years. Increased cost-containment pressures will focus attention not only on improvements in hip fracture treatment but also on prevention. Three approaches that can prevent hip fractures--preventing falls, preventing and treating bone fragility, and using external hip protectors--are reviewed. Although it is impossible to prevent all hip fractures, these methods may significantly reduce the annual incidence of these fractures.     

Laboratory and clinical studies on tazobactam/piperacillin in the field of pediatrics

Laboratory and clinical studies on tazobactam/piperacillin (TAZ/PIPC), a combination drug of piperacillin (PIPC) with the new beta-lactamase inhibitor tazobactam (TAZ), were carried out in the field of pediatrics. 1. After intravenous administration of TAZ/PIPC at a dose of 25 mg/kg to one child, the peak plasma levels of TAZ and PIPC were 24.4 micrograms/ml and 119 micrograms/ml respectively after 5 min. The half-lives of TAZ and PIPC were 0.48 and 0.60 hours respectively. Same as 50 mg/kg to two children, the peak plasma levels of TAZ and PIPC were 17.5, 32.2 micrograms/ml and 92.8, 163 micrograms/ml after 5 min. The half-lives of TAZ and PIPC were 0.37, 0.50 hours and 0.51, 0.59 hours. A ratio of TAZ to PIPC was about 1 to 4 in plasma levels. The cumulative urinary recovery rates of TAZ and PIPC in the first 6 hours after intravenous administration were 15.8, 64.9% and 39.8, 53.4%. 2. The antibacterial activity of TAZ/PIPC against clinically isolated organisms was determined. The MICs of TAZ/PIPC were < or = 0.05 microgram/ml against Haemophilus influenzae and Streptococcus pneumoniae and > or = 1.56 micrograms/ml against Escherichia coli, Staphylococcus aureus and Haemophilus parainfluenzae. 3. The clinical efficacy of TAZ/PIPC could be evaluated in 14 patients with various bacterial infections, and was evaluated as "excellent" in 9 patients and as "good" in 5. The overall clinical efficacy rate in 14 cases was 100% and excellent was 64.3%. Bacteriological efficacy rate was 91.7% (10/11). 4. As a side effect, loose stool was observed in one case, no abnormal laboratory test values were observed. It has been concluded that TAZ/PIPC was a useful drug in the field of pediatrics.     

Pharmacodynamic interactions of ciprofloxacin, piperacillin, and piperacillin/tazobactam in healthy volunteers

Mathematical modeling methods were used to study pharmacokinetic and pharmacodynamic interactions of the antimicrobial combinations piperacillin plus ciprofloxacin and piperacillin plus tazobactam. Twelve healthy volunteers received the following treatments: piperacillin (4 g), ciprofloxacin (400 mg), piperacillin (4 g) plus ciprofloxacin (400 mg), and piperacillin (4 g) plus tazobactam (0.5 g), via intravenous infusion in a four-period crossover design. Serum drug concentrations were analyzed by means of high-performance liquid chromatography (HPLC), and inhibitory titers were performed against eight organisms. The pharmacodynamic response (growth or no growth) was modeled for each of the monotherapy courses using a Hill-type model where Emax was 1 (100% probability of no growth [P(NG)]), and EC50 was the concentration associated with a 50% P(NG). For piperacillin plus ciprofloxacin, P(NG) was a function of 1) plasma concentrations for both drugs; 2) EC50 values from the monotherapy courses; and 3) theta, an interaction term that accommodates synergy, additivity, or antagonism. For piperacillin/tazobactam, the serum ultrafiltrate area under the inhibitory curve was compared with that of piperacillin alone to determine the benefit of tazobactam. The interaction between piperacillin and ciprofloxacin was additive. The addition of tazobactam to piperacillin was beneficial against certain organisms. The model developed can be used to evaluate the activity of combination regimens against representative pathogens.     

Superior effect of tazobactam/piperacillin compared to piperacillin on beta-lactamase-producing Pseudomonas aeruginosa

The potential for modulating gene expression by the use of antisense oligonucleotides has become increasingly interesting in recent years. Antisense oligonucleotides are complementary nucleic acid fragments that hybridize to target sequences within RNA to form a DNA-RNA duplex, resulting in the block of translation of messenger RNA into the protein. Advances in chemistry and molecular biology have provided the basis to develop antisense oligodeoxynucleotides and improve their selectivity, stability and specificity of action. The antisense technology has been extensively used in vitro and in vivo as a tool to study the regulatory mechanisms in biologic processes and as potential therapeutic agents in cancer, viral infections and genetic disorders. In the present review, the various approaches for the use of antisense molecules in oncology, virology, genetic and inflammatory diseases are described; several studies, supporting the in vitro and in vivo applications of this technology, are also presented. Moreover, the potential clinical use of antisense therapies is discussed.     

Pharmacokinetic and clinical studies on biapenem (L-627) in the pediatric field

Pharmacokinetic and clinical studies on biapenem (L-627), a newly developed carbapenem, were performed and the following results were obtained. 1. Absorption/excretion: Pharmacokinetics of biapenem was studied in 14 children at doses of 6 mg/kg and 12 mg/kg administered through 30 minutes-drip infusion. Peak plasma levels and plasma half-lives of the 2 doses were 22.5, 29.9 micrograms/ml, and 0.84, 0.85 hours, respectively. Their urinary recovery rates were 54.5 to 76.1% and 37.3 to 59.5%, respectively. Cerebrospinal fluid levels of biapenem in two patients with purulent meningitis were 0.88 and 2.72 micrograms/ml, and the penetration rates were 3.7 to 8.3%. 2. Clinical study: Forty-nine patients were treated with biapenem at doses exceeding 90 to 100 mg/kg/day for purulent meningitis and at doses between 15.0 and 36.0 mg/kg/day for other infections. Biapenem gave "Excellent" or "Good" responses in 48 cases, hence an efficacy rate of 98.0% was obtained. Only one patient with pneumonia showed a fair response. No adverse reactions were observed. Abnormal laboratory test results were noted in 7 patients including elevation of GOT, GPT, and eosinophils. In no cases the treatment had to be discontinued.     

Inhibition of the renal excretion of tazobactam by piperacillin

A 1:4 by weight of combination of tazobactam, a new beta-lactamase inhibitor, and piperacillin, is now under development in Japan. After bolus iv administration of the combination to beagle dogs, piperacillin both significantly raised the area under plasma concentration time curve (AUC0 approximately infinity) and significantly decreased the total body clearance (Cltot) of tazobactam. The percentage binding of tazobactam and piperacillin to dog and human serum protein was the same for the combination as for the individual compounds. Piperacillin significantly decreased the renal clearance (Clr) and the clearance ratio (Cr) of tazobactam in dogs. Further, probenecid significantly decreased Clr of both tazobactam and piperacillin, and the Cr of tazobactam and piperacillin approximately reached unity. These results indicate that piperacillin inhibits the renal excretion of tazobactam. Both tazobactam and piperacillin are secreted by a tubular anion transport system which is identical to the probenecid secretion system.     

In vitro activity of piperacillin/tazobactam against recent clinical isolates from hospitalized patients in ten Belgian hospitals

This review assesses the usefulness of beta-blockers in the treatment of aggression and describes the parameters for their clinical use. A Medline search using the terms "beta-blockers," "aggression," "propranolol," and "brain injury" identified relevant journal articles published in English between 1977 and 1993. Open, prospective and double-blind, placebo-controlled studies, as well as case reports, were included. Beta-blockers appear to be effective in decreasing the frequency and intensity of aggressive outbursts associated with a wide variety of conditions, such as dementias, attention-deficit disorder, personality disorders, Korsakoff's psychosis, posttraumatic stress disorder, schizophrenia, profound mental retardation, autism, and brain injury. A general discussion attempts to resolve some of the issues surrounding the possible mechanisms of beta-blocker effects, reviews the anatomic and neurochemical bases of aggression, and explores implications of the clinical use of beta-blockers.     

Pharmacokinetic and clinical evaluations of fluconazole in pediatric patients

Fluconazole (FLCZ) is a novel antifungal agent and available both in oral and intravenous forms. It is characterized by a long plasma half-life and a good absorbability into tissues. Because of these, it is expected to be used safety and to exhibit good clinical efficacy in the deep seated mycosis of children. We evaluated the efficacy of FLCZ given orally or intravenously to 6 patients. Pathogenic fungi isolated from all patients were Candida, and diagnosises made were candidemia in 3 cases, gastro-intestinal candidiasis in 2 and skin candidiasis. The clinical efficacies of FLCZ in 5 cases were excellent in 2 cases of gastro-intestinal candidiasis and poor in 3 cases of candidemia. None of the patients reported any side effect. In clinical laboratory tests, no abnormalities that were judged to be related to FLCZ were noted. In the study, clinical efficacy was shown to be poor in candidemia, because these cases had severe underlying diseases and the proper therapy was started too late. Thus earlier diagnosis and earlier treatment seem to be important for FLCZ to exhibit good clinical efficacy in the treatment of deep-seated mycosis.     

Bacteriological, pharmacokinetic and clinical evaluation of azithromycin in the pediatric field]

Azithromycin (AZM), a new macrolide antibiotic, in fine granules and in capsules was studied for pharmacokinetic and clinical evaluation in the pediatric patients. Antibacterial activity of AZM against 43 clinical isolates: AZM exhibited slightly lower activity against Gram-positive bacteria and 2-8-fold higher activity against Gram-negative bacteria than erythromycin or clarithromycin. Plasma or urine samples were collected from eight patients receiving the drug in fine granular form, and two patients receiving it in capsules for the determination of drug levels. The elimination half-lives of AZM after administration at dose of 10 mg/kg/day for 3 days were 50.0 and 51.2 hours for fine granules, and 41.5 hours for capsules. AUC0-infinity was 11.7 and 24.3 micrograms.hr/ml for fine granules, and 8.3 micrograms.hr/ml for capsules. The cumulative excretion rates up to 120 hours after the start of treatment were 8.24 and 13.84% for fine granules, and 3.83% for capsules. AZM was administered to 123 patients once daily at 3.7-20.0 mg/kg body weight over 3 to 5 days with reference to the standard dose of 10 mg/kg. The drug was used to treat patients with pharyngitis, tonsillitis, scarlet fever, pneumonia, mycoplasmal pneumonia, chlamydial pneumonia, otitis media, pertussis, intestinal infection, and SSTI. The effectiveness of AZM was evaluated in 109 cases. The drug was rated "excellent" in 65.1% of the patients and "good" in 29.4%, resulting in an efficacy rate of 94.5%. Furthermore, AZM eradicated 43 of 46 (93.5%) bacteria that had been identified before the treatment. Three patients complained of side effects of urticaria (1 case) and diarrhea (2 cases). Abnormal laboratory changes were reported as follows: decreased leukocyte (3 cases), increased eosinophil (5), increased platelet (2), increased eosinophil and platelet, elevated GPT (1), and elevated GOT and GPT (1). The abnormalities, however, were mild enough to raise no clinically significant problems. In conclusion, AZM in once daily regimen was effective and safe in treatment of pediatric infections.     

Kinetics of piperacillin and tazobactam in ventricular cerebrospinal fluid of hydrocephalic patients

OBJECTIVE: The purpose of this study was to determine, among six second-trimester maternal serum analytes, the best three-analyte combination for fetal Down syndrome detection. STUDY DESIGN: With use of commercially available assay kits, medians for free beta-human chorionic gonadotropin, CA 125, and dimeric inhibin A were established in stored sera from 45 to 50 euploid pregnancies at each week of gestation from 14 to 22 weeks and from 33 Down syndrome pregnancies. Maternal serum alpha-fetoprotein, unconjugated estriol, and intact human chorionic gonadotropin levels measured in each sample before storage were retrieved. All 20 possible three-analyte combinations were evaluated in the multiple-marker screening test for Down syndrome. RESULTS: The mean maternal age of the study population was 35.6 +/- 5.3 years. The best three-analyte combination was maternal serum alpha-fetoprotein, free beta-human chorionic gonadotropin, and dimeric inhibin A: 97% of Down syndrome cases were detected at a false-positive rate of 16%. At a slightly higher false-positive rate (18%) maternal serum alpha-fetoprotein, estriol, and intact human chorionic gonadotropin detected only 79% of cases. CONCLUSIONS: Of six second-trimester maternal serum analytes, the best three-analyte combination for fetal Down syndrome detection was maternal serum alpha-fetoprotein, free beta-human chorionic gonadotropin, and dimeric inhibin A. This retrospective analysis should now be confirmed prospectively.     

Pharmacokinetic and clinical evaluation of azithromycin in pediatrics

Azithromycin (AZM), a new macrolide antibiotic, in fine granules and in capsules was administered at a standard dose of 10 mg/kg once daily for 3 days to pediatric patients with bacterial infections. AZM was studied for its pharmacokinetic and clinical evaluation. 1. AZM possessed potent activity against Gram-positive bacteria and Gram-negative bacteria that had been clinically isolated. 2. Plasma samples were collected from two patients diagnosed as having pneumonia or enteritis, and urine samples were collected from one patient diagnosed as having pneumonia for drug level determination. The drug concentrations in plasma were 0.095 and 0.204 microgram/ml just before the end of treatment, and 0.017 and 0.096 microgram/ml at 48 hours post-treatment. The drug concentrations in urine were 5.16 micrograms/ml and 5.63 micrograms/ml during a period between 24 and 48 hours and between 48 and 72 hours after the start of treatment, respectively. 3. The drug was found effective in 37 of 38 cases with various pediatric infections. AZM treatment eradicated bacteria in 17 of 30 strains (56.7%). 4. One patient complained of mild vomiting, while abnormal laboratory test results indicating mild eosinophilia were reported in four cases.     

Multicentre survey of the comparative in-vitro activity of piperacillin/tazobactam against bacteria from hospitalized patients in the British Isles

In five experiments, in which subjects were to identify a target word as it was gradually clarified, we manipulated the target's frequency of occurrence in the language and its neighborhood size--the number of words that can be constructed from a target word by changing one letter, while preserving letter position. In Experiments 1-4, visual identification performance to screen-fragmented words was measured. In Experiments 1 and 2, we used the ascending method of limits, whereas Experiments 3 and 4 presented a fixed-level fragment. In Experiment 1, there was no relation between overall accuracy and neighborhood size for words between three and six letters in length. However, more errors of commission (guesses) were made for high-neighborhood words and more errors of omission (blanks) were made for low-neighborhood words. Letter errors within guesses occurred at serial positions having many neighbors, and these positions were also likely to contain consonants rather than vowels. In Experiment 2, a small facilitatory effect of neighborhood size on both high- and low-frequency words was found. In contrast, in Experiments 3 and 4, using the same set of words, inhibitory effects of neighborhood size, but only for low-frequency words, were found. Experiment 5, using a speeded identification task, showed results parallel to those of Experiments 3 and 4. We suggest that whether neighborhood effects are facilitatory or inhibitory depends on whether feedback allows subjects to disconfirm initial hypotheses that the target is a high-frequency neighbor.     

Pharmacokinetic and clinical evaluation of cefozopran in premature and newborn patients

Cefozopran (SCE-2787, CZOP), which is already on the market with a variety of approved indications in infectious diseases for adult patients, was administered to premature and newborn patients to evaluate the pharmacokinetics and the clinical efficacy. 1. Pharmacokinetics CZOP was intravenously administered at doses of 10.0 mg/kg, 21.4 mg/kg and 40.0 mg/kg to premature and newborn patients, and the blood concentrations and urinary excretion rate were examined. The blood CZOP concentrations were 31.7 and 65.5 micrograms/ml at 30 minutes after administration of 10.0 mg/kg and 40.0 mg/kg, respectively. The elimination half life was 1.78 hours and 2.31 hours, and the urinary recovery was 110.7% and 53.7% within 6 hours after administration, respectively. In the patient given 21.4 mg/kg, the blood CZOP concentration was 36.4 mg/kg at 1 an hour after administration and the elimination half life was 3.97 hours. The urinary recovery was 29.6% within 5 hours after administration. 2. Clinical results The clinical efficacy was evaluated in 19 patients and judged "good" or better in 13 of them with the efficacy rate or 68.4%. The bacteriological response was evaluated in 10 patients from whom Gram-positive cocci of S. aureus (6 strains), S. pneumoniae (1 strain) and E. faecalis (1 strain) and Gram-negative bacilli of H. influenzae (2 strains) and E. coli (2 strains) were isolated as possible causative organisms. With exception of 1 strain each of S aureus and H influenzae, which were not tested after the treatment with CZOP, all of these strains were found to be eradicated. 3. Adverse drug reactions (ADRs) of signs and symptoms and abnormal alterations of laboratory test values. Safety evaluation was made in 24 patients. ADRs of signs and symptoms were recognized in none of them. As abnormal alterations of laboratory test values, increased eosinophils in 3 patients, elevated GOT in one and elevated GPT in one were recognized. These results indicate that CZOP is a drug useful for treatment of infections in premature and newborn patients.     

Pharmacokinetic/pharmacodynamic evaluation of systemic effects of flunisolide after inhalation

The pharmacokinetics and pharmacodynamics of flunisolide were studied in healthy volunteers after inhalation. In the morning on the day the study began, volunteers inhaled 0.5 mg of flunisolide with and without oral administration of charcoal, or 1 mg, 2 mg, and 3 mg of flunisolide with concomitant administration of charcoal. A placebo group was used to assess the endogenous cortisol, granulocyte, and lymphocyte baseline levels. Flunisolide plasma levels were determined by high-performance liquid chromatography using a tandem mass spectrometer as detector (HPLC/MS/MS). Cortisol plasma levels and differential white blood cell counts were obtained over 12 hours. An integrated pharmacokinetic/pharmacodynamic (PK/PD) model was applied to link the flunisolide plasma concentrations with the effects on lymphocytes, granulocytes, and cortisol. Maximum concentration levels of 3 to 9 ng/mL of flunisolide were observed after 0.2 to 0.3 hours for all of the investigated doses. The terminal half-life ranged from 1.3 to 1.7 hours. There was no statistical difference between treatments in the presence or absence of orally administered charcoal. The pharmacokinetic/pharmacodynamic (PK/PD) models satisfactorily described the time-courses of the effects on granulocytes, lymphocytes, and cortisol suppression. The resulting E50-values (concentrations to induce 50% of the maximum effect) concurred with the reported values of in vitro receptor binding affinities. The duration of the systemic effects were short because of the short half-life of the drug. Cumulative cortisol suppression increased with dose administration and ranged from 20% to 36%. The PK/PD simulations resulted in a smaller degree of cortisol suppression for the drug administered at 10 PM. The cumulative change from baseline was slightly smaller for the effects on granulocytes and lymphocytes than those on cortisol. This information promotes the comparison with other inhaled glucocorticoids.     

Pharmacokinetic analysis of gentamicin thrice and single daily dosage in pediatric cancer patients

Fifty-two children suffering from different types of malignancies were included and evaluated for the pharmacokinetics of gentamicin thrice or single daily dosage protocols. All the study population received a total dose of 5 mg/kg daily. Thirty children received gentamicin thrice daily, and 22 were treated using the single daily protocol; all had fever and neutropenia when included. The individual pharmacokinetic parameters were calculated using a one-compartment model for two blood gentamicin samples. The mean (SD) t 1/2 (h), clearance (mL/min/BSA), Vss (L/kg), Cmax (micrograms/mL), and Cmin (micrograms/mL) were 3.05 (1.0) and 3.9 (0.6) h, 136 (61.3) and 99.9 (65.3) mL/min/BSA, 0.4035 (0.167) and 0.457 (0.17) L/kg, 5.2 (2.0) and 11.5 (4.2) micrograms/mL, 0.8 (0.6) and 0.18 (0.1) microgram/mL for thrice and single daily dosage schedules, respectively. The single gentamicin daily dose protocol had a significantly longer t 1/2, shorter clearance normalized to BSA, higher Cmax, and lower Cmin in comparison with the thrice daily schedule. We recommend the use of gentamicin at 5 mg/kg daily delivered as a single daily dose for pediatric cancer patients with fever and neutropenia, in spite of the measured pharmacokinetic differences, which in our opinion have no clinical significance.     

Pharmacokinetic approach to the clinical use of lidocaine intravenously

The time course of lidocaine plasma concentrations following various modes of administration were predicted by computer. Initiating therapy with a single intravenous bolus dose was unsatisfactory; plasma levels during the first hour were potentially toxic after a 200-mg bolus and subtherapeutic after a 50- to 100-mg bolus. After two bolus doses of 100 mg, separated by 20 to 30 minutes, or a rapid loading infusion over 15 to 60 minutes, therapeutic concentrations were achieved and maintained. Pharmacokinetic principles can be of value in devising rational approaches to lidocaine dosage.