Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part II).
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Aging↗
Biomedical subjects
T Mazzei
Publications and source records attributed to T Mazzei.
Pharmacokinetics, endocrine and antitumour effects of leuprolide depot (TAP-144-SR) in advanced prostatic cancer: a dose-response evaluation.
Twenty-two patients with advanced prostatic cancer and one with benign prostatic hypertrophy were given the GnRH analogue leuprolide in the form of a slow-release depot formulation by subcutaneous injection at doses of 3.75, 7.5, 15 or 30 mg. Following the first dose, drug levels were measured by a double-antibody RIA over an observation period of 5 weeks. Thereafter patients continued long-term subcutaneous treatment at the same dose every 4 weeks. Serum levels of leuprolide showed a rapid increase immediately after injection, reaching a peak proportional to dose within 3 h (range of mean values 13.1-54.5 ng/ml). Subsequently, mean drug levels declined to a plateau proportional to dose (0.49-1.99 ng/ml at 5 weeks). A significant dose-dependent increase in the area under the serum concentration-time curve from zero to 35 days (AUC0-35 days) from 541.7 to 1653.9 ng/ml.h was also noted (p less than 0.01). With all doses there was an initial rise in serum LH and FSH, followed by a rise in testosterone and dihydrotestosterone, then a sharp decrease within 3 weeks. FSH inhibition was achieved in all the 20 evaluable patients and was maintained in 17 of them (85%) over 5 weeks. Fifteen subjects (75%) had marked suppression of LH levels. In 13 of them (65%) this condition continued for the entire observation time. Castration levels of serum testosterone and dihydrotestosterone, however, were maintained in all patients for up to 5 weeks. Two of the 21 evaluable patients (10%) had a complete response; 15 a partial response (71%) and 3 stable disease (14%). No significant differences were observed in relation to dose. Clinical improvement and serum hormonal changes support this as a new and superior method of administration of leuprolide at a dose as low as 3.75 mg.
Aged↗
Clinical pharmacokinetics and tissue penetration of teicoplanin.
The pharmacokinetic properties were investigated of teicoplanin, including its penetration into suction blister fluid (SBF), after a single intravenous bolus administration of 600 mg in seven pneumological patients with normal renal and hepatic function. Blood and SBF samples were collected during the 60-hour period drug administration. Teicoplanin was assayed microbiologically and the mean serum concentration at the end of the i.v. injection was 98.7 +/- 16 mg/l falling to 2.3 +/- 0.4 mg/l at 60 h. The antibiotic was rapidly distributed into a fast equilibrating peripheral compartment and, at a lower rate, into a slowly equilibrating peripheral compartment, while the mean elimination half-life (t1/2 beta) was 34.1 +/- 6.8 h. Penetration into the SBF, though slow, was good, reaching a mean peak level of 8.7 +/- 1.7 mg/l at a mean time of 2.1 h, with a penetration index (obtained by percentage ratio of the area under curve in the SBF to that of serum) of 42.9%.
Adult↗
Pharmacokinetics of teicoplanin during cardiopulmonary bypass surgery.
Teicoplanin is a recently introduced long-acting glycopeptide antibiotic effective against Gram-positive aerobic and anaerobic bacteria. The effects of hypothermic extracorporeal circulation on teicoplanin serum pharmacokinetics have been studied in 18 patients undergoing open-heart surgery for coronary artery bypass graft or prosthetic cardiac valve insertion. The patients received a single 600 mg dose of teicoplanin by intravenous (i.v.) bolus (five cases) or by i.v. infusion over 20 min (13 cases) approximately 1 h before the anticipated skin incision and 2 h before the anticipated extracorporeal circulation. Serum drug concentrations were measured by a microbiological method using Bacillus subtilis ATCC 6633 as the test organism. Following i.v. bolus injection and i.v. infusion, teicoplanin levels in serum (mean +/- s.d.) were respectively 13.9 +/- 6.8 and 11.4 +/- 2.4 mg/l at the beginning of extracorporeal circulation, 8.8 +/- 3.5 and 10.2 +/- 2.3 mg/l at the end of this procedure and 2.8 +/- 0.6 and 2.9 +/- 1.0 mg/l at 24 h after surgery. Mean AUCs were 378.1 +/- 52.5 and 328.9 +/- 88.0/l.h and mean elimination half-life values were 27.9 +/- 12.7 and 30.3 +/- 11.0 h, respectively under the same conditions. These differences in plasma pharmacokinetic parameters were not significant. Teicoplanin pharmacokinetics in patients undergoing cardiopulmonary bypass surgery were similar to those observed in non-surgical patients with normal renal and hepatic function, confirming experimental evidence for lack of effects of extracorporeal circulation.
Bacterial Infections↗
Impaired polyglutamylation of methotrexate as a cause of resistance in CCRF-CEM cells after short-term, high-dose treatment with this drug.
Two methotrexate-resistant sublines, CCRF-CEM R3/7 and CCRF-CEM R30/6, were selected from the human leukemia T-lymphoblast cell line, CCRF-CEM, after repeated exposures (7 and 6 times, respectively) for 24 h to constant concentrations (3 and 30 microM) of the drug. Analysis of the mechanism of resistance revealed no differences in levels of dihydrofolate reductase activity, its binding affinity for methotrexate, or in methotrexate transport between the CCRF-CEM parent and methotrexate-resistant cell lines. The development of resistance to methotrexate was associated with a marked decrease in the intracellular level of methotrexate polyglutamates. Although the resistant sublines were able to form substantial amounts of folate polyglutamates when measured with [3H]folic acid, the level of polyglutamates formed was decreased to about 50% of that formed by the parent cell line. No qualitative differences in folate polyglutamates formed were noted between the parental and resistant sublines. This is the first example of a cell line which displays resistance which is solely attributable to defective methotrexate polyglutamate synthesis.
Drug Resistance↗
Impaired methotrexate polyglutamylation in a human leukemia cell line resistant to short-term, high-dose methotrexate.
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Cell Line↗
Comparison of the antimicrobial prophylactic efficacy of cefotaxime and cephazolin in obstetric and gynaecological surgery. A randomised multicentre study.
A prospective randomised multicentre study was designed to assess the efficacy of 2 different cephalosporins as short term prophylactic treatment in obstetric and gynaecological surgery. A single dose of cefotaxime (2g IV before surgery) was compared with 2 doses of cephazolin (2g IV before surgery and after 8 hours). Patients exposed to antibacterial drugs within 7 days, who had preoperative infections, or with known beta-lactam hypersensitivity were excluded. 612 patients entered the study, of whom 552 were evaluable. 276 were given cephazolin (group A) and 276 cefotaxime (group B). Groups A and B were similar for mean age, obesity, diabetes, types of diseases and obstetric history. No significant differences were observed in type of surgery (vaginal hysterectomy, abdominal hysterectomy, myomectomy and caesarean section) between 2 groups. The mean duration of surgery was 89 and 85 minutes in group A and B, respectively. 25 patients (9.1%) in group A and 20 (7.2%) in group B developed wound infections (not statistically significantly different). The percentages of patients with infections other than surgical infections were similar (i.e. 13.0 and 11.2 for the cefotaxime and the cephazolin groups, respectively). These preliminary data show that a single 2g IV dose of cefotaxime and two 2g IV doses of cephazolin have equal antimicrobial prophylactic activity in obstetric and gynaecological surgery.
Adult↗
Prophylaxis in gynaecological and obstetric surgery: a comparative randomised multicentre study of single-dose cefotetan versus two doses of cefazolin.
Antimicrobial prophylaxis is recommended in all clean-contaminated surgery where the critical threshold of number and virulence of the contaminating organisms with respect to host resistance is reached. Obstetric and gynaecological surgery is clean-contaminated and risk of infection due to aerobic and anaerobic bacteria without prophylaxis can be quantified at 30-40% for vaginal hysterectomy, 10-35% for abdominal hysterectomy and 10-34% for caesarean section. To assess the role of two different cephalosporins as short term prophylaxis, we carried out a multicentre randomised study involving a single 2 g i.v. dose of cefotetan in comparison with two doses of cefazolin (2 g i.v. before surgery and after 8 hours). Criteria for exclusion were: exposure to antibiotics within 7 days, preoperative infection, hypersensitivity to beta-lactams. Four hundred and sixty patients entered the study, of which 229 received cefotetan and 231 cefazolin. No significant differences in mean age, obesity, preoperative weight loss, diabetes, type of disease, type of surgery (vaginal or abdominal hysterectomies and caesarean sections) and number of pregnancies and abortions existed between the two groups of patients. The total rate of infected patients undergoing hysterectomy was 8.6% (13/151) in the cefotetan group and 17.4% (29/167) in the cefazolin group (p less than 0.05). This difference was due to cases of symptomatic bacteriuria and antibiotic retreatment, while wound infections were not significantly different (2.6% and 1.8% respectively). Among patients undergoing caesarean section, 9 of 78 (11.5%) and 7 of 64 (10.9%) were infected following cefotetan and cefazolin, respectively (not significant). Cefotetan mean tissue concentrations in gynaecological organs were higher than those of cefazolin (25.5-44.8 vs. 7.4-9.5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Ceftizoxime concentrations in human aqueous humor following intravenous administration.
The aqueous humor penetration of the third-generation cephalosporin, ceftizoxime, was determined in 21 patients awaiting cataract extraction, after an intravenous bolus injection of 2 g. The beta-lactam compound achieved a mean peak aqueous humor concentration of 7.8 mg/l two hours after administration with a serum/humor percent ratio ranging between 7 and 16% during the four-hour sampling interval. Therefore, ceftizoxime levels in this extravascular fluid were above the minimum inhibitory concentrations for the majority of sensitive organisms.
Adult↗
Effects of 5-methyltetrahydrofolate on the activity of fluoropyrimidines against human leukemia (CCRF-CEM) cells.
The growth inhibitory effects of 5-fluorouracil (FUra) or 5-fluoro-2'-deoxyuridine (FdUrd) combined with 5-methyltetrahydrofolate (5-CH3-H4PteGlu) were determined, as a function of time, dose, and sequence of exposure, on human T-lymphoblast leukemia cells, CCRF-CEM. Synergistic inhibitory effects on cell growth were obtained when exponentially growing CCRF-CEM cells were exposed to 5-CH3-H4PteGlu (1-100 microM) for 4 hr and to FUra (250 microM) or FdUrd (0.5 microM) during the last 2 hr. Synergism was dependent on 5-CH3-H4PteGlu dose (100 greater than 10 greater than 1 microM) and did not occur at 0.1 microM. No clear dependence of synergism on sequence was observed with FUra and 5-CH3-H4PteGlu combinations (5-CH3-H4PteGlu----FUra,5-CH3-H4PteGlu + FUra, or FUra----5-CH3-H4PteGlu). With 5-CH3-H4PteGlu and FdUrd combinations, synergism was dependent on sequence of exposure (5-CH3-H4PteGlu + FdUrd, 5-CH3-H4PteGlu----FdUrd were synergistic, but FdUrd----5-CH3-H4PteGlu was not). Thymidine (0.1 microM), added after drug treatment, substantially rescued CCRF-CEM cells from 5-CH3-H4PteGlu----FUra cytotoxicity. L-methionine (1500 mg/l) completely protected CCRF-CEM cells from enhanced cytotoxicity of the combination, 5-CH3-H4PteGlu-FdUrd. The results are consistent with the hypothesis that the mechanism by which 5-CH3-H4PteGlu potentiates fluoropyrimidine cytotoxicity is the enhancement of complex formation between thymidylate synthase and 5-fluorodeoxyuridylate, as a consequence of an increase of intracellular levels of 5,10-methylenetetrahydrofolate generated from 5-CH3-H4PteGlu. Also, enhanced stability of the complex in the presence of high levels of this folate coenzyme may contribute to the synergism observed. These data provide a rationale basis for further trials of folate coenzymes and fluoropyrimidine combinations in the clinic.
Antineoplastic Combined Chemotherapy Protocols↗
Pharmacokinetics of roxithromycin in renal and hepatic failure and drug interactions.
In patients with renal insufficiency roxithromycin pharmacokinetic parameters are significantly altered. In particular, the Cmax, the AUC and the T1/2 are increased and the Clr is reduced. In alcoholic cirrhotic patients the blood half-life is dosage higher than in normals. In spite of this, in these types of patients the usual roxithromycin dosage should not be modified. Potential pharmacokinetic drug interactions that involve roxithromycin are very few and concern only disopyramide and theophylline. Theophylline concentrations should be monitored if the pretreatment blood level is greater than 15 mg/l.
Aged↗
Principles of antimicrobial chemoprophylaxis in surgery.
In the last fifteen years great efforts have been made to establish the appropriate use of antimicrobial agents in surgery. The most common error in the use of prophylactic antibiotics is to continue the drugs beyond the time necessary for maximal benefit: the smallest dose of the drug should be given over the shortest period of time which results in a low rate of postoperative septic complications. In the selection of appropriate antimicrobial drugs for prevention or therapy of surgical infections the most important pharmacological and clinical factors affecting the choice are considered.
Anti-Bacterial Agents↗
Comparative in vitro activity of ciprofloxacin, ofloxacin and pefloxacin against resistant clinical isolates.
The in-vitro antimicrobial activity of three new quinolones, ciprofloxacin, ofloxacin and pefloxacin, was compared against 194 recent clinical isolates, 50 S. aureus, 50 E. coli, 45 E. cloacae and 49 P. aeruginosa. About half of the strains were resistant to a standard reference antibiotic like oxacillin (S. aureus), ampicillin (E. coli), gentamicin (E. cloacae) and amikacin (P. aeruginosa). The resistant selected strains were less susceptible to the three fluoroquinolones tested than the parent isolates, but, except for pefloxacin against E. cloacae and P. aeruginosa, the decrease in susceptibility was relatively low and MICs remained below the resistance break-point.
Anti-Bacterial Agents↗
Ciprofloxacin inhibition of cefoxitin betalactamase induction in an Enterobacter cloacae strain.
The betalactamase activity of an Enterobacter cloacae strain was measured using subinhibitory concentrations of cefoxitin and ciprofloxacin respectively as enzyme inducer and induction inhibitor. Cultures of this strain were also exposed to different ceftriaxone concentrations either alone or in the presence of cefoxitin and/or ciprofloxacin. Ciprofloxacin at subinhibitory concentrations does not interfere with ceftriaxone's activity and is capable of neutralizing the antagonistic effect of cefoxitin on ceftriaxone. The enzyme assay and MS-2 System demonstrate ciprofloxacin's partial suppression of cefoxitin betalactamase induction in the E. cloacae strain tested.
Cefoxitin↗
Microbiological and pharmacokinetic evaluation of cefonicid, a long-acting cephalosporin.
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Bacteria↗
Microbiological and pharmacokinetic evaluation of cefonicid, a long-acting cephalosporin.
The in vitro antimicrobial activity of cefonicid has been tested against 27 recent clinical isolates of 7 different species (S. aureus, E. coli, K. pneumoniae, P. mirabilis, S. marcescens, E. cloacae and P. aeruginosa) using the MS-2 Research System, contrast phase microscopy and the colony forming unit assay. With the exception of P. aeruginosa, S. marcescens and E. cloacae, cefonicid showed excellent activity against the different bacterial species tested (i.e. S. aureus, E. coli, K. pneumoniae and P. mirabilis). Tissue penetration of cefonicid after a single i.m. or i.v. dose (1 or 2 g, respectively) was also studied using the suction blister method. In 14 adult subjects with normal renal and liver functions, cefonicid plasma half-life was 5.1 and 5.4 h following i.v. and i.m. administration. Drug concentrations achieved at peak in plasma and suction blister fluid were higher than the minimum inhibitory concentrations for most sensitive pathogens and remained above these values for 24 h. These data support the use of a single daily dose regimen of cefonicid, both i.v. and i.m., for the treatment of most common infections caused by sensitive pathogens in blood and tissues.
Bacteria↗
Perioperative chemotherapy in the treatment of carcinoma of the uterine cervix.
Two hundred forty-eight women from 1969-71 who underwent surgery for carcinoma of the cervix and were treated with triaziquone (0.2 mg i.v. daily) from day 2-5 after the operation, are compared to a group of 301 conventionally treated patients examined over the 3 following years. Survival rates after 5 years did not differ significantly between the 2 groups of patients, considered either globally or divided according to their clinical or surgical-pathological stage. The incidence of complications in the "treated" patients was not significantly higher, particularly considering local and general post-operative recovery. A prospective randomized study using drugs with a high cytotoxic activity in patients with tumors limited to the cervix and unfavorable prognostic factors, could in the future help evaluate the possibility of using surgical adjuvant chemotherapy in carcinoma of the cervix.
Adult↗
First-line combination chemotherapy with mitoxantrone and cyclophosphamide in advanced breast cancer.
In this study, 30 evaluable patients with advanced carcinoma of the breast were treated with cyclophosphamide 600 mg/m2 i.v. followed one day later with mitoxantrone (Novantrone; dihydroxyanthracenedione) 16 mg/m2 i.v. Drug treatment was repeated every 3-4 weeks, for a maximum of 12 cycles. The overall response rate was 43%; five of 30 patients (16%) attained a complete remission, and eight of 30 (27%) had a partial remission. Median response duration was 12+ months. The greater number of responses was seen in skin and soft tissues. Hematologic toxicity was limiting with 75% of patients experiencing substantial-severe leukopenia. Clinically evident heart failure developed in one patient; in three other patients there was minor-moderate alteration of cardiac function during mitoxantrone-cyclophosphamide therapy. Based on these data, it is believed that this regimen may provide significant long-lasting palliation in patients with advanced breast cancer.
Adult↗