Search

To assess whether gene methylation in peritoneal fluid (PF) is clinically feasible for determining micrometastasis to the peritoneum in gastric cancer. The gene methylation of BNIP3, CHFR, CYP1B1, MINT25, SFRP2, and RASSF2 were analyzed in 107 specimens of PF by quantitative methylation-specific polymerase chain reaction. All patients were placed into one of 3 groups: group A (n = 42), patients with depth of cancer invasion at muscularis propria (MP) or less than MP; group B (n = 45), depth of cancer invasion beyond the MP; and group C (n = 20), histologically diagnosed peritoneal metastasis or cancer cells cytologically defined in the peritoneal cavity. Patients in both groups A and B were diagnosed as having no cancer cells by peritoneal cytology and histology. The methylation status of the 6 genes was found to be significantly different among the 3 groups (group A, 0–5%; group B, 0–15%; group C, 15–45%; P

Miocamycin (midecamycin acetate), an oral macrolide, has a 16-membered ring and, in vitro, a similar or greater spectrum of activity to that of erythromycin. It is active against erythromycin-resistant staphylococcal and streptococcal species that express inducible-type resistance, has rapid and extensive penetration into body tissues and fluids, a low potential for drug interactions and is well tolerated.

Macrolide antibiotics can interact adversely with commonly used drugs, usually by altering metabolism due to complex formation and inhibition of cytochrome P-450 IIIA4 (CYP3A4) in the liver and enterocytes. In addition, pharmacokinetic drug interactions with macrolides can result from their antibiotic effect on microorganisms of the enteric flora, and through enhanced gastric emptying due to a motilin-like effect. Macrolides may be classified into 3 different groups according to their affinity for CYP3A4, and thus their propensity to cause pharmacokinetic drug interactions. Troleandomycin, erythromycin and its prodrugs decrease drug metabolism and may produce drug interactions (group 1). Others, including clarithromycin, flurithromycin, midecamycin, midecamycin acetate (miocamycin; ponsinomycin), josamycin and roxithromycin (group 2) rarely cause interactions. Azithromycin, dirithromycin, rikamycin and spiramycin (group 3) do not inactivate CYP3A4 and do not engender these adverse effects. Drug interactions with carbamazepine, cyclosporin, terfenadine, astemizole and theophylline represent the most frequently encountered interactions with macrolide antibiotics. If the combination of a macrolide and one of these compounds cannot be avoided, serum concentrations of concurrently administered drugs should be monitored and patients observed for signs of toxicity. Rare interactions and those of dubious clinical importance are those with alfentanil and sufentanil, antacids and cimetidine, oral anticoagulants, bromocriptine, clozapine, oral contraceptive steroids, digoxin, disopyramide, ergot alkaloids, felodipine, glibenclamide (glyburide), levodopa/carbidopa, lovastatin, methylprednisolone, phenazone (antipyrine), phenytoin, rifabutin and rifampicin (rifampin), triazolam and midazolam, valproic acid (sodium valproate) and zidovudine.

The renewed interest in macrolide antibacterials with expanded indications for clinical use, as well as their markedly increased usage, justifies the continuous search for new compounds designed to offer the patient not only enhanced bioavailability but also a reduced incidence of adverse effects. Macrolides are an old and well established class of antimicrobial agents that account for 10 to 15% of the worldwide oral antibiotic market. Macrolides are considered to be one of the safest anti-infective groups in clinical use, with severe adverse reactions being rare. Newer products with improved features have recently been discovered and developed, maintaining or significantly expanding the role of macrolides in the management of infection. This review deals with the tolerability of the clinically available macrolide antibacterials. With the exception of drug interactions, adverse effects have been analysed during the last 40 years in many thousands of adult and paediatric patients. Recently developed derivatives have been compared with the older compounds, and the expected and well assessed adverse effects have been set apart from those which are unusual, very rare or questionable. Gastrointestinal reactions represent the most frequent disturbance, occurring in 15 to 20% of patients on erythromycins and in 5% or fewer patients treated with some recently developed macrolide derivatives that seldom or never induce endogenous release of motilin, such as roxithromycin, clarithromycin, dirithromycin, azithromycin and rikamycin (rokitamycin). Except for troleandomycin and some erythromycins administered at high dose and for long periods of time, the hepatotoxic potential of macrolides, which rarely or never form nitrosoalkanes, is low for josamycin, midecamycin, miocamycin, flurithromycin, clarithromycin and roxithromycin; it is negligible or absent for spiramycin, rikamycin, dirithromycin and azithromycin. Transient deafness and allergic reactions to macrolide antibacterials are highly unusual and have definitely been shown to be more common following treatment with the erythromycins than with the recently developed 14-, 15- and 16-membered macrolides. There have been case reports in the literature of 51 patients during the last 30 years who experienced uncommon or dubious adverse effects after treatment with older compounds and in which there appears to be strong evidence of a causal relationship with the drug. Only 3 cases had an unfavourable outcome, and these were patients administered erythromycin lactobionate intravenously too rapidly or at high dose. Targets of these occasional reactions are generally the heart, liver and central nervous system. Other unusual organ pathologies are related to immunomediated disorders more than to primary parenchymal toxicity, or to the rarely serious consequences of macrolide-induced alterations in intestinal microflora.(ABSTRACT TRUNCATED AT 400 WORDS)

The pharmacokinetic and microbiological data of roxithromycin, an oral semisynthetic macrolide, and its clinical use in respiratory infections in Japanese patients are reviewed. In healthy men the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of roxithromycin increase with increasing dosage, as does urinary drug excretion. The drug’s Cmax and half-life are increased compared with erythromycin, josamycin and miocamycin. Maximum sputum and plasma drug concentrations were higher in patients with chronic bronchitis receiving roxithromycin 150mg than in those receiving erythromycin 400mg. Uptake of roxithromycin into polymorphonuclear cells was proportionally greater than that of erythromycin and josamycin. Roxithromycin showed good in vitro activity against respiratory pathogens, including intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae, although it had only about one-quarter of the activity of erythromycin against Staphylococcus aureus and Streptococcus pneumoniae. High success rates were obtained in patients with acute pneumonia (79%) and chronic obstructive airways disease (75%) receiving roxithromycin in a noncomparative trial in 378 patients with respiratory tract infection, and roxithromycin and miocamycin showed similar efficacy in a double-blind study.

The activity in vitro of clarithromycin, a new macrolide, was compared to that of various antibiotics in tests using 3,880 clinical isolates. Clarithromycin was two times more active than erythromycin againstStaphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, streptococci of groups C, G and F,Brucella melitensis, Legionella pneumophila andMycoplasma spp., 16 times more active againstUreaplasma urealyticum and 2 to 4 times less active againstCampylobacter spp. In general, clarithromycin showed intrinsic activity 2 to 4 times higher than that of roxithromycin and 4 to 8 times higher than that of miocamycin. Cross-resistance was found between the macrolides. Clarithromycin was bactericidal againstStreptococcus spp. andHaemophilus influenzae.

The pharmacokinetics of rokitamycin tablets were studied in 12 healthy volunteers in a randomized cross-over design. The doses tested were 200 mg, 300 mg, 400 mg and 600 mg, as single oral administration. Rokitamycin was absorbed quickly with Tmax for all doses around 30 min after drug intake. Total AUC and Cmax values were linearly related to the administered dose. The buffer formulation determined a low interindividual variation. The overall findings show a good similarity with the data obtained in Japanese subjects. Tolerability was very good.

Medifoxamine is a monoamine reuptake inhibiting antidepressant drug. We have investigated its pharmacokinetics in normal healthy volunteers. After an overnight fast, ascending doses of 200, 500, 750 and 1000 mg of medifoxamine were taken orally. Plasma samples were analysed using a specific HPLC method. Medifoxamine was well tolerated and exhibited a first order linear pharmacokinetic profile. It underwent rapid absorption and peak plasma concentrations were achieved about 1.0 h after administration. Thereafter the elimination profile was biphasic with a mean terminal half life less than 3 hours. We found a linear relationship (r = 0.80) between administered dose and AUC values for the four doses. High values were obtained for the apparent volumes of distribution and the plasma clearance.

The influence of treatment with ponsinomycin, a new macrolide antibiotic, on the pharmacokinetics of cyclosporin A has been studied in 10 renal transplant patients. The pharmacokinetics of cyclosporin A was investigated at steady state, before and during treatment with ponsinomycin. On average, the blood levels of cyclosporin A were doubled by the macrolide, possibly due to a decrease in elimination or/and to an increase in absorption. Ponsinomycin should be use very carefully in patients treated with cyclosporin A.

The interaction between a new macrolide antibiotic, miocamycin, and theophylline was evaluated in a single cross-over study in 5 asthmatic children. Each patient received a single dose of theophylline (4.3 mg/kg) delivered in 15 min using a constant-rate infusion pump, immediately before and after a 10 day course of miocamycin 17.5 mg/kg b.d. The pharmacokinetics of theophylline were calculated for each phase of the study. The elimination rate constant (3.92 vs 3.74 h-1), the mean total body clearance (1.71 vs 1.8 ml X min X kg-1) and the mean apparent volume of distribution (0.57 vs 0.581 X kg-1) did not differ. The result can be explained by the inability of the antibiotic to form inactive cytochrome P-450 metabolite complexes which can interfere with the metabolism of theophylline. Thus, miocamycin can safely be administered to asthmatic children requiring theophylline treatment, when they have an infection due to susceptible pathogens.

The pharmacokinetic aspects in humans of macrolide antibiotics that are currently or soon to be on the market (i.e. erythromycin, oleandomycin, spiramycin, josamycin, midecamycin, miocamycin, rosaramycin, roxithromycin and azithromycin) are reviewed. Macrolide antibiotics are basic compounds, poorly soluble in water, which are mostly absorbed in the alkaline intestinal environment. They are acid unstable, but the newer semisynthetic derivatives (i.e. roxithromycin and azithromycin) are characterised by increased stability under acidic conditions. Macrolides are highly liposoluble and consequently penetrate well into tissue, especially bronchial secretions, prostatic tissue, middle ear exudates and bone tissues, as evidenced by tissue/serum concentration ratios greater than 1. They do not penetrate well into the CSF. Macrolides undergo extensive biotransformation in the liver. With a few exceptions (e.g. miocamycin), the metabolites of these drugs are characterised by little or no antimicrobial activity. Plasma protein binding is variable from one compound to another. At therapeutic concentrations, protein-bound erythromycin accounts for 80 to 90% of the total drug present in the blood, and the fraction is 95% for roxithromycin. The lowest values of protein-bound fraction are observed for midecamycin and josamycin (about 15%), and intermediate values are reported for spiramycin and miocamycin. However, the clinical relevance of this parameter is not clearly established. Plasma half-life (t½) values vary for the macrolides described: erythromycin, oleandomycin, josamycin and miocamycin have a t½ ranging from 1 to 2 hours; spiramycin, erythromycin stearate, the mercaptosuccinate salt of propionyl erythromycin and rosaramicin have an intermediate t½ (about 7, 6.5, 5 and 4.5 hours, respectively); the newer semisynthetic compounds roxithromycin and azithromycin are characterised by high t½ values (i.e. 11 and 41 hours, respectively). Under normal conditions, the major route of elimination is the liver. Renal elimination also takes place but it contributes to total clearance only to a small degree, as evidenced by low renal clearance values. The degree of modification of macrolide pharmacokinetics by renal insufficiency or hepatic disease is usually not considered clinically relevant, and no recommendation for dose modification is necessary in these patients. The pharmacokinetics of macrolides are modified in elderly patients. Accordingly, their use must be accompanied by a closer than usual clinical monitoring of the older patient. Clinically the newer semisynthetic macrolides, such as roxithromycin, possess an antibacterial spectrum at least equivalent to that of erythromycin, and superior pharmacokinetic properties (i.e. longer elimination half-life, higher tissue penetration) over erythromycin and other macrolides, allowing longer intervals between doses.

The influence of ponsinomycin on the pharmacokinetics of theophylline has been studied in 12 young healthy volunteers. They received 10 doses of theophylline 200 mg every 8 h p.o., successively in the absence and then in the presence of ponsinomycin. This new macrolide, structurally related to midecamycin, was given in the therapeutic dose of 800 mg b.d. for 5 days, starting 2 days before the second phase of treatment with theophylline. The pharmacokinetic parameters of theophylline, calculated from its plasma concentration at steady-state, were not affected by the co-treatment. In particular, there was no significant difference between the peak and trough plasma levels, apparent clearance or apparent elimination half-life of theophylline in the absence and the presence of ponsinomycin. Only renal clearance was slightly (27%) but significantly increased by the co-treatment. The results suggest that ponsinomycin would be a good choice if a macrolide antibiotic were needed in patients being treated with theophylline.