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PubMed2006

Mechanisms of venoocclusive disease resulting from the combination of cyclophosphamide and roxithromycin.

BACKGROUND: High doses (>or=500 mg/m) of cyclophosphamide are known to cause venoocclusive disease (VOD). The authors recently observed a patient treated with immunosuppressive cyclophosphamide doses (100 mg/day) and roxithromycin who developed VOD. Because roxithromycin inhibits cytochrome P450 (CYP) 3A4 and P-glycoprotein, the patient may have been exposed to higher cyclophosphamide and/or cyclophosphamide metabolite concentrations. METHODS: The effect of roxithromycin on the metabolism and toxicity of cyclophosphamide was studied using human hepatic microsomes and a human endothelial cell line. RESULTS: Cyclophosphamide or roxithromycin at concentrations from 0.05 to 500 micromol/L were not toxic to endothelial cells as assessed by lactate dehydrogenase (LDH) leakage assay. However, the combination of roxithromycin (500 micromol/L) and cyclophosphamide was toxic for all the tested cyclophosphamide concentrations (0.05 to 500 micromol/L) without clear concentration dependence (LDH ratio 38.3 +/- 11.0 [mean +/- SEM] for the combination with cyclophosphamide 0.05 micromol/L and 50.2 +/- 10.2 for the combination with cyclophosphamide 500 micromol/L; P <or= 0.005 for all tested combinations vs. control). Although roxithromycin did not favor the generation of toxic metabolites from cyclophosphamide, it led to cyclophosphamide accumulation due to inhibition of both CYP3A4 and CYP2B6. Although roxithromycin inhibited P-glycoprotein, this was not the mechanism by which cyclophosphamide toxicity was increased because cyclophosphamide in combination with other P-glycoprotein inhibitors was not toxic to endothelial cells. In the presence of roxithromycin (500 micromol/L), cyclophosphamide (500 micromol/L) induced apoptosis in endothelial cells (34.3 +/- 10.4% apoptotic cells [in % of total cells] for the combination of cyclophosphamide and roxithromycin, 0.7 +/- 0.25% for cyclophosphamide alone, 0% for roxithromycin alone; P < 0.0001) most probably by mitochondrial membrane permeability transition and release of cytochrome c. CONCLUSIONS: The combination cyclophosphamide and roxithromycin, but not the individual compounds, is toxic to endothelial cells by inducing apoptosis. Inhibition of P-glycoprotein and formation of toxic metabolites are unlikely causes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1987

Roxithromycin in nongonococcal urethritis.

This presentation is a summary of five different studies on the efficacy and tolerance of roxithromycin in the treatment of non-gonococcal genital infections. Three of the studies were double-blind comparative and two were open studies. Of the 924 out-patients whose data were analysed for clinical efficacy, 637 received treatment with roxithromycin 150 mg bd. The standard dose of roxithromycin, 150 mg bd for ten days, was compared with doxycycline 200 mg daily, lymecycline 300 mg bd and roxithromycin 450 mg once daily. The overall clinical success rate was 90% (576 of 637 patients) for roxithromycin 150 mg bd. In the three comparative trials, no significant difference was found between the clinical success rates of roxithromycin 150 mg bd and the other drugs. The overall clinical success rate with roxithromycin 150 mg bd was 92% (512/558) in nongonococcal urethritis and 81% (64/79) in cervicovaginitis. Taking into account all patients treated with roxithromycin 150 mg bd, the bacteriological success rate was 90% (444/492). In the comparative trials, no significant difference could be found between the treatment groups. Roxithromycin 150 mg bd was effective in eradicating 97% (308/316) of the isolates of Chlamydia trachomatis, 88% (149/170) of Ureaplasma urealyticum, 73% (40/55) of Mycoplasma hominis and 57% (13/23) of Gardnerella vaginalis. The present findings show that a high cure rate can be achieved with a ten-day course of treatment with roxithromycin and that it is at least as effective as the tetracyclines commonly used in the treatment of nongonococcal urethritis. A higher dosage than 300 mg/day of roxithromycin did not offer any clear advantage in terms of efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1995

Prevention of Pneumocystis carinii pneumonia and of cerebral toxoplasmosis by roxithromycin in HIV-infected patients.

The prevention of cerebral toxoplasmosis and of Pneumocystis carinii pneumonia is an essential objective in the management of patients infected with HIV. Given that roxithromycin is active in vitro against Toxoplasma gondii and that in 1989 Dolermann reported the effective treatment of P. carinii respiratory infections with erythromycin, a randomized pilot study was undertaken in 52 patients infected with HIV. Patients were treated with either: a monthly dose of pentamidine aerosol (300 mg); roxithromycin once a week (300 mg t.i.d.); or a combination of pentamidine aerosol and roxithromycin. Intention to treat analysis was applied to these 52 patients, all of whom received at least one treatment dose. Five out of 18 patients treated with pentamidine aerosol, 1/17 patients treated with pentamidine aerosol + roxithromycin and none of the 17 patients treated with roxithromycin developed cerebral toxoplasmosis (p = 0.038). P. carinii pneumonia was diagnosed in one patient in the pentamidine aerosol-treated group, in one patient treated with roxithromycin and in none of the patients treated with pentamidine aerosol + roxithromycin (non-significant difference). Four cases of Mycobacterium tuberculosis and Mycobacterium avium-intracellulare infection were seen in the pentamidine aerosol-treated group (p = 0.028) and none in the roxithromycin groups. Adverse events leading to the discontinuation of treatment occurred in 5/34 (14.7%) patients treated with roxithromycin. Nausea, abdominal pain and raised transaminases occurred in four patients and a skin allergy in the final patient. Roxithromycin appears to be effective in the prevention of pulmonary pneumocystis infection and of cerebral toxoplasmosis in HIV-infected patients. However, these results require confirmation in a larger study.

AIDS-Related Opportunistic Infections↗

PubMed2007

Roxithromycin inhibits tumor necrosis factor-alpha-induced matrix metalloproteinase-1 expression through regulating mitogen-activated protein kinase phosphorylation and Ets-1 expression.

BACKGROUND AND OBJECTIVE: In periodontitis, matrix metalloproteinases (MMPs) are upregulated in response to locally released inflammatory cytokines, resulting in pathologic processes. Roxithromycin is a 14-membered ring macrolide antibiotic with broad-spectrum antibacterial effects against oral pathogens and immunomodulatory effects. Recently, we reported that roxithromycin inhibits tumor necrosis factor (TNF)-alpha-induced vascular endothelial growth factor expression in human periodontal ligament (HPDL) cell cultures. In the present study, we examined the effect of roxithromycin on TNF-alpha-induced MMP-1 production by HPDL cells. MATERIAL AND METHODS: Cultured cells were incubated with 1% fetal bovine serum for 24 h, followed by treatment with 10 ng/ml TNF-alpha, 10 microM roxithromycin, and mitogen-activated protein kinase inhibitor at various concentrations. Culture supernatants and sediments were collected at different time-points and used for enzyme-linked immunosorbent assays, and northern and western blot analyses. RESULTS: In HPDL cell cultures, roxithromycin strongly inhibited TNF-alpha-induced MMP-1 mRNA expression and production. The inhibition of MMP-1 gene expression by roxithromycin was dependent on de novo protein synthesis and was regulated at the transcriptional level. Roxithromycin significantly inhibited TNF-alpha-induced c-Jun N-terminal kinase activation (JNP) and marginally inhibited extracellular signal-regulated kinase (ERK) 1/2 activation, but not p38 mitogen-activated protein kinase activation. Furthermore, roxithromycin reduced the induction of Ets-1, one of the critical factors in MMP-1 transcription. CONCLUSION: Roxithromycin inhibits TNF-alpha-mediated MMP-1 induction through the downregulation of ERK1/2 and JNK activation and the subsequent reduction of Ets-1, suggesting that roxithromycin may have therapeutic use in periodontitis and other chronic inflammatory conditions involving MMP-1 induction.

Adult↗

PubMed1998

Metabolism of roxithromycin in the isolated perfused rat liver.

Roxithromycin is a macrolide antibiotic with high clinical potency. N-Demethylation is considered to be one of the main pathways of roxithromycin metabolism in rats. We have studied the hepatic metabolism of roxithromycin in the isolated perfused rat liver. After addition of roxithromycin (30 microM) to the perfusion medium the parent compound and one major metabolite were detected in bile by high-performance liquid chromatography. The metabolite was identified as monodesmethylated roxithromycin by mass spectrometric analysis. Onset of biliary excretion of native roxithromycin was fast, reaching a maximum (130.52 +/- 43.88 pmol g(-1) min(-1)) after only 10 min, whereas excretion of the metabolite was delayed (maximum 75.83 +/- 11.92 pmol g(-1) min(-1) at 30 min). The cumulative excretion of roxithromycin and its metabolite into bile during the 60 min of application amounted to only 1.09 +/- 0.30 and 0.64 +/- 0.22% of the roxithromycin cleared from the perfusate during the same time. The liver content was 0.48 micromol (g liver)(-1), indicating high retention within the organ. No release of the metabolite into the perfusate was detected. In conclusion, this study has demonstrated the importance of phase-I metabolism for the biliary excretion of roxithromycin in rat liver. These findings might be predictive of roxithromycin biotransformation and biliary excretion in man.

Animals↗

PubMed1987

In-vitro comparison of roxithromycin and erythromycin against 900 anaerobic bacterial strains.

The in-vitro antibacterial activity of roxithromycin was assessed by an agar dilution method against 900 recent clinical anaerobic isolates by five laboratories in England, France, Germany and Japan. Roxithromycin had similar activity to erythromycin against most anaerobic bacteria, the latter being slightly more active against Gram-negative bacilli. Roxithromycin inhibited 53% of the Bacteroides fragilis group strains; the noticeable exception was Bact. thetaiotaomicron, only 17% of strains of which were inhibited by 4 mg/l roxithromycin. In contrast, all isolates of Bacteroides, other than the Bact. fragilis group, and all Mobiluncus isolates were inhibited by 2 mg/l of roxithromycin or less. This compound was inactive against half the Fusobacterium strains. Roxithromycin and erythromycin inhibited 65 and 72%, respectively, of 436 strains of Gram-negative anaerobes (MIC less than or equal to 4 mg/l). Roxithromycin suppressed 97% of non-sporulating Gram-positive to bacilli, 86% of Peptococcoaceae and 95% of clostridia. Two-thirds of Clostridium difficile strains were susceptible to roxithromycin (MIC less than or equal to 1 mg/l). The activity of roxithromycin against Gram-positive bacilli was identical to that of erythromycin. Overall a concentration of 4 mg/l roxithromycin and erythromycin inhibited 79 and 83%, respectively, of the strains investigated.

Bacteria, Anaerobic↗

PubMed2003

Roxithromycin promotes lymphocyte apoptosis in Dermatophagoides-sensitive asthma patients.

A new macrolide, roxithromycin, may be an effective treatment for asthma. Lymphocyte apoptosis is impaired in patients with asthma, while spontaneous apoptosis increases during remission, and such changes may be involved in the onset and remission of mite-sensitive asthma. Lymphocyte apoptosis was evaluated by incubating cells from patients with asthma in the presence of roxithromycin. Low concentrations of roxithromycin (1-500 ng/ml) augmented the early, but not late, phase of apoptosis in Dermatophagoides farinae-stimulated peripheral blood mononuclear (PBM) cells, while high concentrations of roxithromycin (1 microg/ml; 6 microg/ml is the maximum serum level) augmented both the early and late phases of apoptosis. In both unstimulated and phytohemagglutinin-stimulated cells, roxithromycin did not significantly affect the induction of apoptosis. In cells from normal subjects, roxithromycin did not affect the induction of apoptosis. Other antibiotics, including cefazolin and ampicillin, did not cause significant induction of apoptosis. Fas ligand, but not Fas receptor, expression on D. farinae-stimulated cells was up-regulated after stimulation with 1 microg/ml roxithromycin, while Bcl-2 expression on both unstimulated and D. farinae-stimulated cells showed a decrease after the same treatment. Roxithromycin can induce apoptosis of D. farinae-activated lymphocytes in patients with D. farinae-sensitive asthma. Induction of the Fas/Fas ligand system and reduced Bcl-2 expression were involved in the promotion of apoptosis by roxithromycin treatment.

Adolescent↗

PubMed2000

Pharmacokinetic interaction between proton pump inhibitors and roxithromycin in volunteers.

BACKGROUND: Triple therapy including two antibiotics and a proton pump inhibitor is a rational approach to the treatment of Helicobacter pylori induced peptic ulcer disease. The interaction of antimicrobial therapy and acid suppression is not yet well elucidated. AIMS: To investigate the effects of proton pump inhibitors on roxithromycin levels in plasma and gastric tissue under steady-state conditions in volunteers. METHODS: In two crossover studies omeprazole 20 mg b.d., lansoprazole 30 mg b.d., roxithromycin 300 mg b.d., and the combination of roxithromycin with either omeprazole or lansoprazole were administered to 12 healthy volunteers over 6 days. Blood plasma levels of the drugs were measured. In addition, roxithromycin concentrations were also determined in gastric juice and gastric tissue obtained during endoscopy. RESULTS: The proton pump inhibitors and roxithromycin did not alter the blood plasma pharmacokinetics of each other. When compared to roxithromycin administered alone, its combination with a proton pump inhibitor significantly increased the roxithromycin concentrations in gastric juice (3.0-5.0 microg/mL vs. 0.3-0.4 microg/mL) and gastric tissue (antrum: 3.8-4.0 vs. 2.8 microg/g, fundus: 5.9-7.4 vs. 4.2-4.4 microg/g). CONCLUSIONS: Proton pump inhibitors and roxithromycin do not alter the systemic bioavailability of each other. However, proton pump inhibitors increase the local concentration of roxithromycin in the stomach which may contribute to the clinically proven synergic beneficial action in eradication therapy of H. pylori.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1998

Experimental evaluation of roxithromycin combined with dapsone or sulphamethoxazole on Pneumocystis carinii and Toxoplasma gondii dual infections in a rat model.

We have developed a dual infection model in immunosuppressed rats for evaluating drugs against Pneumocystis carinii and Toxoplasma gondii, two important opportunistic pathogens in patients with AIDS. Using this model, we reported that the macrolide roxithromycin was effective at a daily dose of 400 mg/kg in preventing the development of T. gondii infection but did not have a prophylactic effect against P. carinii in the same rats. A lower dose (200 mg/kg/day) had only marginal effects. Extending these experiments, we have now shown that roxithromycin at doses of 400 or 200 mg/kg/day combined with dapsone at doses of 5, 25 or 50 mg/kg/day completely prevented the development of T. gondii infection, with no parasites being detected in any of the tissues sampled. Roxithromycin at either dose combined with dapsone at 25 or 50 mg/kg/day was also effective in preventing the development of P. carinii infection in the lungs. The lowest dose of dapsone (5 mg/kg/day) was not fully effective. Pyrimethamine-dapsone, a combination used clinically, was tested in the same experiment, and gave results comparable to those with roxithromycin-dapsone combinations. In a further experiment combining roxithromycin with sulphamethoxazole, roxithromycin was effective in preventing the T. gondii infection, even when given at only 200 mg/kg/day with 20 mg/kg/day of sulphamethoxazole. When the dose of sulphamethoxazole was reduced to 2 mg/kg/day and given with roxithromycin 200 mg/kg/day, T. gondii infection developed in two of the five rats treated. P. carinii infection was prevented by sulphamethoxazole at 20 mg/kg/day but not completely by 2 mg/kg/day. Roxithromycin also has activity against Mycobacterium avium, another important cause of opportunistic infections in AIDS patients, and the compound penetrates mammalian cells well. Taken together with the favourable pharmacokinetic profile of roxithromycin, these results suggest that it may have a clinical utility, when used with other agents, in controlling the development of opportunistic infections caused by M. avium complex, T. gondii and P. carinii in HIV-infected individuals.

Animals↗

PubMed2004

pH-dependent geometric isomerization of roxithromycin in simulated gastrointestinal fluids and in rats.

The biotransformation of roxithromycin in simulated gastrointestinal fluids at 37 degrees C and in rats was investigated by using liquid chromatography-tandem mass spectrometry. Roxithromycin degraded to its Z-isomer and decladinose derivative in simulated gastrointestinal fluids in vitro at pH </= 3, and followed pseudo first-order degradation with a rate constant (+/-SD, standard derivation) of 0.1066 min(-1) (+/-0.0014) at pH 1.0, 0.0994 min(-1) (+/-0.0031) at pH 1.2, 0.0400 min(-1) (+/-0.0003) at pH 1.3, 0.0136 min(-1) (+/-0.0008) at pH 1.8, and 0.0022 min(-1) (+/-0.0002) at pH 3.0, respectively. The ratio of Z-roxithromycin to roxithromycin (+/-SD) was 0.21 (+/-0.01) at pH 1.0, 0.19 (+/-0.03) at pH 1.2, 0.18 (+/-0.01) at pH 1.3, 0.15 (+/-0.01) at pH 1.8, and 0.08 (+/-0.02) at pH 3.0, respectively. Pepsin and NaCl added to gastric fluid had no effect on the transformation of roxithromycin. Roxithromycin underwent four metabolic routes such as geometric isomerization, demethylation, dealkylation, and hydrolysis of cladinose in rats after oral administration. The geometric isomerization in rats was neither observed after an intravenous dose, nor after an oral dose with Na(2)CO(3) alkalization. The geometric isomerization between roxithromycin and its Z-isomer took place in gastric fluid both in vitro and in vivo. It was interconvertible and pH-dependent. The isomerization of roxithromycin to its Z-isomer was less than that of Z- to E-configuration both in vitro and in vivo.

Animals↗

PubMed1999

Inhibitory effects of roxithromycin on tumor angiogenesis, growth and metastasis of mouse B16 melanoma cells.

We examined the effects of roxithromycin, a 14-membered ring macrolide antibiotic, on tumor angiogenesis, tumor growth and metastasis of mouse B16BL6 melanoma cells. The inhibitory effect of roxithromycin on angiogenesis using mouse dorsal air sac model was dose-dependent, and 100 mg/kg of roxithromycin administered intraperitoneally twice a day reduced the dense capillary network area to about 20% of the control. Administration of roxithromycin histologically reduced the development of microvessels and mononuclear cell infiltration. In vivo tumor growth studies demonstrated that intraperitoneal administration of roxithromycin at 20 mg/kg/day and 50 mg/kg/day reduced tumor size of B16BL6 melanoma to about 56% and 33% (experiment 1), 71% and 48% (experiment 2) of that in the respective controls. Roxithromycin also significantly inhibited pulmonary metastasis of B16BL6 cells in a spontaneous system. The inhibitory activities of roxithromycin on angiogenesis, tumor growth and metastasis were compared with those of a potent angiogenesis inhibitor, TNP-470. These data demonstrated that roxithromycin has potent antiangiogenic and antitumor effects and might have possible therapeutic applications.

Air Sacs↗

PubMed1999

Anti-inflammatory effect of roxithromycin in patients with aspirin-intolerant asthma.

BACKGROUND: Fourteen-membered macrolides, such as roxithromycin, have been reported to exhibit other pharmacological activity including anti-asthmatic effects, besides antibiotic activity. OBJECTIVE: This study was designed to investigate the protective effect of roxithromycin on airway responsiveness to the sulpyrine provocation test and to investigate whether this protective activity is associated with a reduction in aspirin-induced excretion of urinary leucotriene E4 (u-LTE4), a marker of cysteinyl leucotriene overproduction that participates in the pathogenesis of aspirin-intolerant asthma. Also, the present study was designed to examine whether or not its anti-asthmatic activity was associated with a reduction in eosinophilic inflammation. METHODS: For 8 weeks before analysis, subjects received 150 mg of roxithromycin or matching placebo twice daily. We assessed the effects of pretreatment with roxithromycin on bronchoconstriction precipitated by inhalation of sulpyrine in 14 adult patients with mild or moderate aspirin-intolerant asthma; those who were in stable clinical condition and were hyperresponsive to sulpyrine provocation test were allocated to this study. A double-blind, randomized, crossover design was used. Urinary LTE4 was measured by a combined reverse-phase high-performance liquid chromatography (rp-HPLC) enzyme immunoassay on sulpyrine provocation testing day. Blood and sputum samples were taken in the morning on the sulpyrine provocation testing day. Eosinophil counting and measurement of eosinophilic cationic protein (ECP) were performed. RESULTS: After the 8 weeks of treatment with roxithromycin, patients' symptoms, blood eosinophils, serum ECP, sputum eosinophils, and sputum ECP were significantly decreased. On the other hand, values of PC20-sulpyrine did not improve after roxithromycin at all. Furthermore, although challenge with sulpyrine caused a significant increase in u-LTE4, pretreatment with roxithromycin or placebo did not affect excretion of u-LTE4. CONCLUSION: Although roxithromycin does not have antileucotriene effects, it has an antibronchial inflammatory effect associated with eosinophilic infiltration. This study raises further interesting therapeutic possibilities and warrants further trials of new approaches to the treatment of aspirin-intolerant asthma.

Adult↗

PubMed1996

An open comparative study of azithromycin and roxithromycin in the treatment of acute upper respiratory tract infections.

An open, multicentre study was undertaken in order to evaluate the efficacies and safety profiles of azithromycin and roxithromycin in 440 adults with acute otitis media, sinusitis or acute beta-haemiolytic streptococcal pharyngitis/tonsillitis. Treatment with 500 mg azithromycin, administered orally once daily for 3 days, produced a satisfactory clinical outcome (cure or improvement) in 51/52 (98%) patients with otitis media, 91/91 (100%) patients with pharyngitis/tonsillitis and 64/68 (94%) patients with sinusitis. Treatment with 150 mg roxithromycin, given orally twice daily for 10 days, produced satisfactory clinical responses in 54/55 (98%), 91/92 (99%) and 69/73 (94%) patients with otitis media, pharyngitis/tonsillitis and sinusitis respectively. Of the 17 azithromycin-treated patients with sinusitis who were clinically and bacteriologically evaluable, Staphylococcus aureus persisted in two and Streptococcus pneumoniae in one. S. aureus also persisted in 1/12 clinically and bacteriologically-evaluable patient treated with roxithromycin. Of the 58 and 64 patients with pharyngitis/tonsillitis treated with azithromycin and roxithromycin, respectively, who were clinically and bacteriologically evaluable, Streptococcus pyogenes persisted at the end of treatment in 7/58 (12%) in the azithromycin group and in 13/64 (20%) in the roxithromycin group. At follow-up, there was no evidence of S. pyogenes reinfection in patients treated with azithromycin. Three episodes of reinfection occurred in the roxithromycin treatment group. Also, three patients showed evidence of clinical relapse at follow-up, although no pathogens were isolated. Azithromycin was associated with a lower incidence of adverse events. No azithromycin-treated patient was withdrawn prematurely because of a treatment-related event. Three roxithromycin-treated patients were withdrawn from treatment because of severe headache, thyroiditis or fatigue. In conclusion, for adults with acute upper respiratory tract infections, a 3-day course of once-daily azithromycin was found to be as effective and as well tolerated as a 10-day course of twice-daily roxithromycin.

Acute Disease↗

PubMed1990

Single oral dose pharmacokinetics of erythromycin and roxithromycin and the effects of chronic dosing.

Roxithromycin is a semisynthetic macrolide antibiotic having similar in vitro antibacterial profile and potency to erythromycin but possibly greater in vivo potency. The single and multiple oral dose pharmacokinetics of roxithromycin and erythromycin were studied in 12 healthy volunteers. Plasma concentrations of the two compounds were measured by a sensitive and specific high-performance liquid chromatographic method using electrochemical detection. After single doses, roxithromycin 150 mg gave a Cmax 3.3-fold higher and an area under the curve (AUC) 16.2-fold higher than erythromycin 250 mg. The half-life for roxithromycin was 12.42 +/- 3.94 h compared with 1.53 +/- 0.42 h for erythromycin. On multiple dosing, the AUC over a dosing interval for erythromycin (250 mg, six hourly doses) was increased 2.3-fold compared with the single dose, whereas that for roxithromycin (150 mg, 12 hourly) was decreased by 25.4%. Because of these opposing changes during chronic dosing, the average plasma roxithromycin concentration over the dosing interval was 2.6-fold higher than that for erythromycin, which was a smaller excess than would have been predicted from the single dose data. The results suggest that roxithromycin exerts less inducing and inhibiting effects on human cytochrome P450 than erythromycin. Roxithromycin has a favorable pharmacokinetic profile suitable for twice daily dosing and may have a lower potential than erythromycin for cytochrome P450-mediated drug interactions.

Adolescent↗

PubMed2005

Roxithromycin inhibits constitutive activation of nuclear factor {kappa}B by diminishing oxidative stress in a rat model of hepatocellular carcinoma.

PURPOSE: Recently, 14-member macrolide antibiotics such as clarithromycin and roxithromycin have been shown to have anticancer and antiangiogenic effects. We investigated the suppressive effect of roxithromycin on accelerated hepatocellular carcinoma growth in a rat hepatocarcinogenetic model and compared results with effects from TNP-470. EXPERIMENTAL DESIGN: Tumor was induced by oral diethylnitrosamine administration for 17 weeks. Normal saline, TNP-470 (50 mg/kg), or roxithromycin (40 or 100 mg/kg) was administered i.p. thrice per week from week 10 to 17. RESULTS: Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Tumor growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of nuclear factor kappaB, and increased lipid peroxidation level. All these effects were absent in animals that received roxithromycin or TNP-470. The inhibitory effect of roxithromycin was dose dependent and no clear differences were noted between groups given roxithromycin 100 mg/kg and TNP-470 50 mg/kg. CONCLUSIONS: Our results indicate that roxithromycin inhibits oxidative stress, nitric oxide production, and nuclear factor kappaB activation induced by experimental hepatocarcinogenesis. The data provide additional evidence for the potential use of roxithromycin in treatment of hepatocellular carcinoma prevention.

Animals↗

PubMed1996

Effects of roxithromycin, erythromycin and troleandomycin on their N-demethylation by rat and human cytochrome P450 enzymes.

1. The effects of treatment of rat with roxithromycin, erythromycin and troleandomycin as well as other chemicals including typical cytochrome P450 inducers were examined in rat and human liver microsomes. 2. Erythromycin and troleandomycin but not roxithromycin caused slight increases in CYP3A1 levels and the N-demethylation of roxithromycin, erythromycin and troleandomycin and oxidation of nifedipine in rat, but none of these chemicals induced significantly CYP2B1 levels or benzphetamine N-demethylation activities. 3. Dexamethasone and pregnenolone 16 alpha-carbonitrile induced CYP3A1 levels and N-demethylation of roxithromycin, erythromycin and troleandomycin but not of benzphetamine, in rat liver microsomes. Treatment of rat with phenobarbital caused increases in both CYP2B1 and 3A1 levels and all of the N-demethylation activities examined. Phenytoin and metyrapone produced increases in contents of 2B1 and activities of benzphetamine N-demethylation as well as of roxithromycin, erythromycin and troleandomycin, although these two inducers did not induce 3A1 protein significantly. 4. In man, a liver sample that was high in CYP3A4 and nifedipine oxidation activity was found to be the most active in N-demethylation activities towards these substrates examined. In addition, recombinant 3A4 catalysed very efficiently the N-demethylation of roxithromycin, erythromycin and troleandomycin in reconstituted monooxygenase systems. 5. These data suggest that erythromycin and troleandomycin, but not roxithromycin, were able to induce CYP3A1 in rat liver microsomes, and that N-demethylation of roxithromycin, erythromycin and troleandomycin were catalysed mainly by 3A1 (and partly by 2B1) in rat and by 3A4 in man.

Animals↗

PubMed1992

Roxithromycin in Lyme borreliosis: discrepant results of an in vitro and in vivo animal susceptibility study and a clinical trial in patients with erythema migrans.

A new semisynthetic macrolide roxithromycin was evaluated for its potential use in the treatment of Lyme borreliosis. Using a macro-dilution broth technique, Borrelia burgdorferi was shown to be susceptible to roxithromycin with a minimal bactericidal concentration (MBC) of 0.06-0.25 microgram/ml. A systemic B. burgdorferi infection was established in gerbils; a dosage of greater than or equal to 25 mg/kg/day roxithromycin for 10 days eliminated the infection. A single blind, randomized multicenter study was performed to evaluate the efficacy of roxithromycin 150 mg b.i.d. versus phenoxymethyl-penicillin 1 g b.i.d. for 10 days in patients with uncomplicated erythema migrans. The study was interrupted when 19 patients had enrolled because of five treatment failures. All 5 patients had received roxithromycin; three patients had persisting or recurrent erythema migrans, one developed a secondary erythema migrans-like lesion and severe arthralgia and one developed neuroborreliosis. B. burgdorferi was isolated from skin biopsies after roxithromycin therapy from two patients with persistent erythema migrans and both isolates were still highly susceptible to roxithromycin (MBC = 0.03 microgram/ml). No treatment failures were seen in 10 patients treated with phenoxymethyl-penicillin. Roxithromycin is thus not recommended for treatment of Lyme borreliosis.

Adult↗

PubMed1998

Comparative studies of in vitro inhibition of cytochrome P450 3A4-dependent testosterone 6beta-hydroxylation by roxithromycin and its metabolites, troleandomycin, and erythromycin.

Roxithromycin has been shown to be a relatively weak inhibitor of cytochrome P450 (P450 or CYP)-dependent drug oxidations, compared with troleandomycin. The potential for roxithromycin and its major metabolites found in human urine [namely the decladinosyl derivative (M1), O-dealkyl derivative (M2), and N-demethyl derivative (M3)] to inhibit testosterone 6beta-hydroxylation after metabolic activation by CYP3A4 was examined and compared with inhibition by troleandomycin and erythromycin in vitro. Of roxithromycin and its studied metabolites, M3 was the most potent in inhibiting CYP3A4-dependent testosterone 6beta-hydroxylation by human liver microsomes and was activated to the inhibitory P450.Fe2+-metabolite complex to the greatest extent. Roxithromycin and its metabolites were N-demethylated by human liver microsomes, although the rates were slower than those measured with troleandomycin and erythromycin as substrates. Recombinant human CYP3A4 in a baculovirus system coexpressing NADPH-P450 reductase was very active in catalyzing the N-demethylation of roxithromycin, M1, and M2, as well as troleandomycin, erythromycin, and M3. The order for inhibition of CYP3A4-dependent testosterone 6beta-hydroxylation activities by these macrolide antibiotics in the recombinant CYP3A4 system was estimated to be troleandomycin > erythromycin >/= M3 >/= M2 > M1 >/= roxithromycin. Erythromycin, roxithromycin, and its metabolites all failed to inhibit CYP1A2-dependent (R)-warfarin 7-hydroxylation and CYP2C9-dependent (S)-warfarin 7-hydroxylation but did inhibit CYP3A4-dependent (R)-warfarin 7-hydroxylation. These results suggest that roxithromycin itself is not as potent an inhibitor of CYP3A4 activities as are troleandomycin and erythromycin, probably because of the slower metabolism of this compound to metabolites M1, M2, and M3 in humans.

Anti-Bacterial Agents↗