Development of a population pharmacokinetic model to describe azithromycin whole-blood and plasma concentrations over time in healthy subjects.

Azithromycin (AZI), a broad-spectrum antibiotic, accumulates in polymorphonuclear cells and peripheral blood mononuclear cells. The distribution of AZI in proinflammatory cells may be important to the anti-inflammatory properties. Previous studies have described plasma AZI pharmacokinetics. The objective of this study was to describe the pharmacokinetics of AZI in whole blood (concentration in whole blood [Cb]) and plasma (concentration in plasma [Cp]) of healthy subjects. In this study, 12 subjects received AZI (500 mg once a day for 3 days). AZI Cb and Cp were quantified in serial samples collected up to 3 weeks after the last dose and analyzed using noncompartmental and compartmental methods. After the last dose, Cb was greater than Cp. Importantly, Cb, but not Cp, was quantifiable in all but one subject at 3 weeks. The blood area under the curve during a 24-h dosing interval (AUC24) was ∼2-fold greater than the plasma AUC24, but simulations suggested that Cb was not at steady state by day 3. Upon exploration of numerous models, an empirical 3-compartment model adequately described Cp and Cb, but Cp was somewhat underestimated. Intercompartmental clearance (CL; likely representing cells) was lower than apparent oral CL (18 versus 118 liters/h). Plasma, peripheral, and cell compartmental volumes were 439 liters, 2,980 liters, and 3,084 liters, respectively. Interindividual variability in CL was low (26.2%), while the volume of distribution variability was high (107%). This is the first report to describe AZI Cb in healthy subjects, the distribution parameters between Cp and Cb, and AZI retention in blood for up to 3 weeks following 3 daily doses. The model can be used to predict Cb from Cp for AZI under various dosing regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01026064.).

The novel antifungal agent PLD-118 is neither metabolized by liver microsomes nor inhibits cytochrome P450 in vitro.

PLD-118 is a novel, oral antifungal drug, under development for the treatment of Candida infections. Possible metabolism of PLD-118 by rat, dog and human S9 liver homogenates and inhibition of human cytochrome P450 (CYP) enzymes were investigated. PLD-118 (10 and 100 microM) incubated for 0-60 min with S9 fractions and NADPH was determined by HPLC, using the Waters AccQ.Tag method after derivatization of amino acids to stable, fluorescent derivatives. CYP assays were performed using pooled human liver microsomes with substrates, selective towards human CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A, incubated at concentrations around the Km. Incubation mixtures were preincubated with PLD-118 (0.1-100 microM) or control inhibitor for 5 min. No metabolism of PLD-118 was detected with rat and dog S9 fractions. A small (8%) decrease in PLD-118 at 100 microM (not detected at 10 microM) with human microsomes was considered to be biologically irrelevant. PLD-118 did not inhibit any of the tested CYPs. PLD-118, at concentrations up to 100 microM, is not metabolized by rat, dog or human liver S9 homogenates and does not inhibit human CYPs in vitro, suggesting little likelihood for interaction of PLD-118 with drugs metabolized by these enzymes.

[Presence of Chlamydia pneumoniae antibodies in patients with ischemic heart disease and acute myocardial infarct]. / Nazocnost protutijela protiv Chlamydia pneumoniae u bolesnika s ishemicnom bolesti srca i akutnim infarktom miokarda.

Numerous seroepidemiological studies that suggest an association of C. pneumoniae infection and atherosclerosis have been published in last decade. The aim of this study was to assess a prevalence of C. pneumoniae antibodies in population of Zagreb area, and to investigate possible differences in prevalence of antibodies in patients with atherosclerosis and healthy controls. Forty-seven patients with coronary artery disease or myocardial infarction and 54 controls without any previous history of atherosclerosis were enrolled in the study. Sera were examined by microimmunofluorescence test. Persons with IgA antibody titers > or = 1:32, and/or IgG antibody titers > or = 1:64 were considered as seropositive. We found 75% seropositive in a total number of subjects, although number of seropositive and higher titers of antibodies were found more often in patients with atherosclerosis compared to control group: 74.5% of IgA seropositive patients versus 33.3% seropositive in control group, and 89.4% of IgG seropositive patients compared to 63% seropositive controls. Chronic (persistent) infections with C. pneumoniae were noted in 74.5% of patients and 33.3% controls.

Azithromycin: single 1.5 g dose in the treatment of patients with atypical pneumonia syndrome--a randomized study.

An open comparative study was undertaken in order to assess the efficacy and safety of a single dose of azithromycin in the treatment of community-acquired atypical pneumonia. A total of 100 adult patients with atypical pneumonia syndrome were randomized to receive 1.5 g of azithromycin as a single dose, or 500 mg once daily for 3 days. The presence of Mycoplasma pneumoniae, Chlamydia pneumoniae, Chlamydia psittaci, Coxiella burnetii, and Legionella pneumophila infection was diagnosed by serological tests. Control clinical examinations were performed 72 h, 10-12 days and 4 weeks after treatment initiation. Among 96 patients (48 in each group) who were evaluable for clinical efficacy M. pneumoniae infection was confirmed in 24, C. pneumoniae in nine, C. psittaci in five, C. burnetii in six, and L. pneumophila in five. Forty-seven patients (97.9%) in each group were cured. Side effects were observed in two patients in the single-dose group, and one patient in the 3-day group. In conclusion, a single 1.5 g dose of azithromycin may be an alternative to the standard 3-day azithromycin regimen in the treatment of outpatients with atypical pneumonia syndrome.

Azithromycin versus amoxicillin/clavulanate in the treatment of acute sinusitis.

PURPOSE: To compare the efficacy and tolerability of a 3-day course of azithromycin with a 10-day course of amoxicillin/clavulanic acid in the treatment of acute sinusitis in adults. PATIENTS AND METHODS: One hundred adult patients with acute sinusitis were included in an open, randomized study. Clinical diagnosis of sinusitis was confirmed by nasal endoscopy, sinus radiography, and (when possible) by culture of sinus aspirate. Patients were randomized to receive azithromycin (500 mg once daily for 3 days) or amoxicillin/clavulanate (625 mg every 8 hours for 10 days). RESULTS: A significantly faster resolution of signs and symptoms of sinusitis was observed in the azithromycin-treated patients. By the end of therapy (days 10-12), 95% of the patients in the azithromycin group and 74% in the amoxicillin/clavulanate group were cured. The remaining patients' conditions were improved. By the follow-up visit, cure was achieved in 98% of the azithromycin-treated patients, and 91% of the amoxicillin/clavulanate-treated patients. Treatment failure was observed in three patients from the amoxicillin/clavulanate group, and relapse occurred in one patient from each group. Bacteriologic eradication was achieved in 23 of 23 and 21 of 24 patients treated with azithromycin and amoxicillin/clavulanate, respectively. Both drugs were well tolerated. Two patients (4%) from the azithromycin group and five patients (10%) from the amoxicillin/clavulanate group reported mild gastrointestinal disturbances. CONCLUSIONS: In adults with acute sinusitis, a 3-day course of azithromycin was as effective and well tolerated as a 10-day course of amoxicillin/clavulanic acid. A significantly simpler dosage regimen and faster clinical effect were the advantages of azithromycin.

The relation between plasma lipid levels and pseudocholinesterase activity in hypothyroidism.

The relation of plasma lipids and pseudocholinesterase (PChE) activity was studied in rats made hypothyroid by treatment with propylthiouracil (0.05% in drinking water for 28 days) and in hypothyroid patients prior and after L-thyroxine-therapy (1. week 25-50 microg, 2.-4. week 100 microg daily). In rats, thyroid hormone deficiency caused a significant increase in plasma and adipose tissue PChE activity as well as total plasma cholesterol (TC) concentration, and a decrease in plasma triglyceride (TG) concentration. In contrast to rats, thyroid-deficient humans demonstrated a decrease in plasma PChE activity and an increase in both TC and TG, in comparison with euthyroid controls. After one month's therapy with L-thyroxine, reversion of PChE activity and lipid concentrations occurred. The opposite changes of PChE elicited by thyroid hormone deficiency in men and rats are similar to the respective changes in lipoprotein lipase (LPL) activity, observed by other authors. The inverse correlation between both PChE and LPL activity and TG concentration suggests that PChE, similarly to LPL, may be involved in TG hydrolysis.

[Patient compliance in the treatment of respiratory tract infections]. / Bolesnikova suradljivost u lijecenju infekcija disnih putova.

The survey on outpatients compliance in the treatment of respiratory tract infections was performed in Croatia during April 1996. A total of 213 physicians, 201 adult patients, and 178 parents of sick children were polled by the appropriate questionnaires. The results have shown that in the treatment of respiratory tract infections physicians commonly prescribe thrice-daily antibiotic regimens for 8-10 days. Concerning patients' knowledge, 85% of patients deem that regularity, and 64% that duration of antibiotic administration influences treatment outcome. Over 80% of patients are compliant with once-or twice-daily regimens, but only 50% take regularly and timely drugs that are dosed every 6 or 8 hours. Common reasons for irregular taking of antibiotics are forgetfulness and dosing during sleeping. In terms of appropriate duration of antibiotic therapy, about 20% of patients usually take antibiotic for 8-10 days, 60% for 5-7 days, and 20% for < or = 4 days. It may be concluded that the patients are poorly compliant with oral antibiotics treatment.

Azithromycin: 3-day versus 5-day course in the treatment of respiratory tract infections in children. Croatian Azithromycin Study Group.

A total of 371 children, aged 6 months to 12 years, with acute otitis media, acute sinusitis, streptococcal tonsillitis/pharyngitis, or pneumonia were included in an open, multicenter study. Among them, 192 children were randomized to receive azithromycin for 3 days (10 mg/kg daily), and 179 for 5 days (10 mg/kg on day 1 and 5 mg/kg on days 2-5). The overall clinical cure rate was 95.7% and 96.1%, and bacteriological eradication rate 90.1% and 94.2% in the 3-day and 5-day groups, respectively. Side effects, mostly mild gastrointestinal disturbances, were observed in 5.3% of children from the 3-day, and 6.7% from the 5-day group. Only in one child (0.3%) was therapy discontinued due to vomiting. The results of this study demonstrate that 3-day and 5-day azithromycin courses have comparable efficacy and tolerability in children with respiratory infections.

Azithromycin in the treatment of pneumonias caused by Chlamydia spp: a retrospective study.

A retrospective study was undertaken in order to compare the efficacy and safety of azithromycin and doxycycline in the treatment of pneumonias caused by Chlamydia spp. Patients with radiologically confirmed pneumonia and positive complement fixation test for chlamydial infection who were hospitalized in the University Hospital of Infectious Diseases, Zagreb during the years 1989-1992 were reviewed. Among them, 83 were treated with azithromycin, given in a total dose of 1.5 g over 5 days (500 mg once daily at day 1 followed by 250 mg at days 2-5, 60 patients) or 3 days (500 mg once daily, 23 patients). Twenty-two patients were treated with doxycycline (100 mg b.i.d. for 10 days). Treatment groups were comparable with respect to age, sex, and severity of signs and symptoms of illness. All the patients were cured. There were no differences in duration of fever after treatment initiation between patients treated with azithromycin (whether pretreated with beta-lactam antibiotics or not) and doxycycline (p > 0.05). In addition, 3- and 5-day azithromycin courses were equally effective (p > 0.05). Both drugs were well tolerated, and only two patients treated with azithromycin reported nausea. It may be concluded that in the treatment of pneumonias caused by Chlamydia spp. azithromycin is as effective and well tolerated as doxycycline.

Pseudocholinesterase in alloxan-diabetic rats.

Pseudocholinesterase (PChE) activity in plasma, liver, pancreas and adipose tissue of alloxan-diabetic rats has been determined. 48 hours after the induction of diabetes an increase of PChE activity in plasma and a decrease in liver and adipose tissue was observed. After that, the activity in plasma remained at the same level, in the liver it slowly rose to the control values and in adipose tissue significantly increased beyond the control values. Significant changes of PChE activity in the pancreas were not noticed. Female rats had higher PChE activity in plasma and liver than the male, but in the pancreas and adipose tissue there were no sex differences. On the basis of our results it seems possible to propose that PChE is synthesized also in adipose tissue, but the synthesis is regulated by different mechanisms than those in the liver.