A genome-wide analysis of targets of macrolide antibiotics in mammalian cells.

Macrolide antibiotics, such as erythromycin and josamycin, are natural polyketide products harboring 14- to 16-membered macrocyclic lactone rings to which various sugars are attached. These antibiotics are used extensively in the clinic because of their ability to inhibit bacterial protein synthesis. More recently, some macrolides have been shown to also possess anti-inflammatory and other therapeutic activities in mammalian cells. To better understand the targets and effects of this drug class in mammalian cells, we used a genome-wide shRNA screen in K562 cancer cells to identify genes that modulate cellular sensitivity to josamycin. Among the most sensitizing hits were proteins involved in mitochondrial translation and the mitochondrial unfolded protein response, glycolysis, and the mitogen-activated protein kinase signaling cascade. Further analysis revealed that cells treated with josamycin or other antibacterial agents exhibited impaired oxidative phosphorylation and metabolic shifts to glycolysis. Interestingly, we observed that knockdown of the mitogen-activated protein kinase kinase kinase 4 (MAP3K4) gene, which contributes to p38 mitogen-activated protein kinase signaling, sensitized cells only to josamycin but not to other antibacterial agents. There is a growing interest in better characterizing the therapeutic effects and toxicities of antibiotics in mammalian cells to guide new applications in both cellular and clinical studies. To our knowledge, this is the first report of an unbiased genome-wide screen to investigate the effects of a clinically used antibiotic on human cells.

Randomized Trial of Clarithromycin for Mediterranean Spotted Fever.

The classic antibiotic treatment for Mediterranean spotted fever (MSF) is based on tetracyclines or chloramphenicol, but chloramphenicol's bone marrow toxicity makes tetracyclines the treatment of choice. However, it is convenient to have alternatives available for patients who are allergic to tetracyclines, pregnant women, and children <8 years old. We conducted a randomized clinical trial to compare clarithromycin with doxycycline or josamycin in the treatment of MSF. Forty patients were evaluated (23 male; mean age, 39.87 years); 13 patients were aged <14 years. Seventeen patients received clarithromycin, and 23 received doxycycline or josamycin. The interval between the onset of symptoms and the start of treatment was 4.04 ± 1.70 days in the clarithromycin group versus 4.11 ± 1.60 days in the doxycycline/josamycin group (P = not significant [NS]). Time to the disappearance of fever after treatment was 2.67 ± 1.55 days in the clarithromycin group versus 2.22 ± 1.35 days in the doxycycline/josamycin (P = NS). The symptoms had disappeared at 4.70 ± 2.25 days in the clarithromycin group versus at 4.75 ± 3.08 days in the doxycycline/josamycin (P = NS). There were no adverse reactions to treatment or relapses in either group. In conclusion, clarithromycin is a good alternative to doxycycline or josamycin in the treatment of MSF.

[DOXYCYCLINE (UNIDOX SOLUTAB®) AND/OR JOSAMYCIN (WILPRAFEN®) IN TREATMENT OF PATIENTS WITH PROSTATITIS IN REAL CLINICAL PRACTICE. RESULTS OF THE TAURUS OBSERVATIONAL PROGRAM].

Treatment of chronic prostatitis is a vital and complicated problem, in which a large number of stamps and "stereotyped" approaches often result in uncured patients. The increasing use of intracellular microorganisms in prostatitis etiology requires a modification in the standard approaches. TAURUS study shows high efficacy of doxycycline (Unidox Solutab®) and/or josamycin (Wilprafen®) in chronic prostatitis. Therapy, studied in this program, according to physicians, was effective in 93.2% of patients. Treatment failure was observed in 1.3% of all patients, another 5.5% of patients had insufficient data for assessment. Low incidence of adverse reactions was observed. In the study population, adverse reactions occurred in 2.6% of patients, of them serious adverse events were registered in 0.7% of patients. The most common adverse event in all treatment groups was diarrhea.

[Is it safe to use josamycin in the obstetrics practice in Russia?].

The present situation with the use of antimicrobial drugs for the management of Chlamydia trachomatis infection during pregnancy in the Russian Federation was evaluated. The efficacy and safety of various macrolides in the treatment of chlamydial infection in practical obstetrics were analyzed. It was conclude that josamycin was inferior to azithromycin by a number of pharmacologic parameters, compliance and safety and therefore should not be used in pregnant women.

[Evaluation of efficacy and safety of josamycin (Vilprafen) in the treatment of patients with community-acquired pneumonia].

Clinical and bacteriological efficacy ofjosamycin (Vilprafen), a macrolide antibiotic, was studied in 30 out- and inpatients at the age of 18 to 68 years (the average of 43.4+/-16.7 years old) with nonsevere (PORT) community-acquired pneumonia in the case histories. Josamycin was administered orally in a dose of 500 mg every 8 hours for 7 to 10 days. The treatment course was 5 to 10 days (the average of 7.7+/-1.3 days). The recovery was stated in 28 (93.3%) patients and the pathogen eradication was recorded in 16 (88.9%) patients. Moderate side effects not requiring discontinuation of the drug use were observed in 3 patients. The results of the treatment were indicative of the josamycin high efficacy in the treatment of the patients with nonsevere community-acquired pneumonia.

Macrolide antibiotics induce apoptosis of human peripheral lymphocytes in vitro.

We previously reported that long-term administration of macrolides (MCL) reduced the number of lymphocytes in bronchoalveolar lavage fluid (BALF) of patients with chronic lower respiratory tract disease. To investigate the anti-inflammatory activity of macrolides, we evaluated their effect on apoptosis of lymphocytes isolated from human peripheral blood. Lymphocytes treated with clarithromycin, azithromycin and josamycin at a final concentration of 200 microg/ml showed positive staining for Annexin V, Fas and Fas ligand using flow cytometry with time at 12-72 h, while other antibiotics did not. Our results suggest that macrolides induce apoptosis of lymphocytes through Fas-Fas ligand pathway and could potentially reduce the number of lymphocytes in the lungs of patients with chronic lower respiratory tract disease.

Parálisis recurrencial, como signo de alarma de un neurinoma del acústico / Relapsing paralysis as an alarm sign for acoustic neurinoma

Presentamos un caso de un hombre de 54 años con una parálisis recurrencial derecha. La resonancia magnética (RMN) mostró una masa en el ángulo pontocerebeloso derecho. Los síntomas clínicos más frecuentes son alteraciones cocleares (hipoacusia, acúfenos...), vestibulares (vértigo, inestabilidad en la marcha...) y de los nervios trigémino y facial. Una parálisis recurrencial como primera manifestación de un neurinoma del acústico es una patología inusual (AU)

Efficacy and tolerability of brodimoprim in otitis.

Eighty adult patients affected by acute bacterial otitis media were selected and randomized into two balanced groups of treatment: 1) brodimoprim 200 mg tablets at the dosage of 2 tablets in single dose on the first day and one tablet on the following days; 2) josamycin 500 mg tablets at the dosage of 3 tablets/day. The average duration of treatment was 8 days: all patients completed the trial. The symptoms were evaluated by score method (on the 3rd, 7th and on the last day of therapy) and a thermometric curve was made daily. Microbiological examination of the exudate was performed in the patients with auricular discharge (28), at the beginning of the treatment and 7 days after the end of therapy. The tolerability was assessed through registration of side effects. Brodimoprim resulted more effective in the reduction of hypoacusis and tinnitus; other symptoms demonstrated higher percentage reductions in the group under brodimoprim therapy. Bacteriological exams were negative at the second checkup, except in 6 patients (3 per group). Side effects were reported in 5 patients (12.5%) treated with brodimoprim and in 9 (22.5%) treated with josamycin. Abnormal values in laboratory tests were not observed.

Josamycin in the treatment of bronchopulmonary infections.

The subjects were 6,033 outpatients, from every province of Spain, with acute bronchitis (44%), exacerbation of chronic bronchitis (35%), typical pneumonia (14%), or atypical pneumonia (8%). Most of the patients were aged 50 to 70 years. The dose of josamycin in over 90% of the patients was 2 gm daily. The mean duration of infection before treatment was 5.3 days and treatment lasted a mean of 9.2 days. Concomitant drugs were taken by 78% of the patients; these included mucolytic agents, xanthine derivatives, beta-adrenergic agonists, and corticosteroids. After two weeks of treatment, the infection was cured in 82% of the patients with acute bronchitis, in 30% with chronic bronchitis, in 85% with typical pneumonia, and in 85% with atypical pneumonia; improvement was shown by 16%, 66%, 13%, and 13%, respectively. Treatment side effects were noted in 11% of the patients receiving josamycin alone and in 17% of the patients receiving concomitant drugs. Most side effects were mild and transient; treatment was discontinued because of side effects in 2% of the patients receiving josamycin alone and in 3% receiving concomitant drugs. It is concluded that josamycin is a safe and effective agent in the treatment of bronchopulmonary infections.

Comparative efficacy and tolerance of erythromycin and josamycin in the prevention of bacteraemia following dental extraction.

The tolerance and pharmacokinetics of erythromycin stearate and josamycin base were compared in healthy dental students. The efficacy and tolerance of the two antibiotics were compared in the prevention of bacteraemia following dental extraction. Erythromycin achieved higher serum levels at the time of extraction in dental patients than did josamycin. Erythromycin was rapidly and better absorbed than josamycin in the student volunteers, but josamycin caused less gastrointestinal side effects than erythromycin. Both antibiotics were only marginally more effective than placebo in preventing bacteraemia following dental extraction.

Efficacy and safety of clarithromycin versus josamycin in the treatment of hospitalized patients with bacterial pneumonia.

The efficacy and safety of 500 mg clarithromycin and 1000 mg josamycin both given twice daily for a maximum of 14 days were compared in the treatment of 72 hospitalized patients with bacterial pneumonia. The predominant pathogens isolated were Streptococcus pneumoniae and Staphylococcus aureus. Clinical success was reported for 91.5% of patients treated with clarithromycin and for 87.0% of those treated with josamycin. Eradication of the causative pathogen was noted in 85.7% of patients receiving clarithromycin and in 90% of those receiving josamycin. Adverse events considered probably to relate to therapy were experienced by 2% of patients treated with clarithromycin and by 12.5% of those treated with josamycin; one patient treated with josamycin was withdrawn because of severe nausea and moderate vomiting. Treatment with clarithromycin at half the dosage of josamycin was found to have comparable efficacy and to be associated with a lower incidence of adverse events.