bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced Cytogenetic and Antineoplastic Effects by the Combined Action of Two Esteric Steroidal Derivatives of Nitrogen Mustards
Authors: Papageorgiou A. , Nikolaropoulos S.S. , Arsenou E.S. , Karaberis E. , Mourelatos D. , Kotsis A. , Chryssogelou E.
Published: April 2003

The authors studied the effect of two modified steroids containing different proportions (%) of alkylating agents alone or in combination on sister chromatid exchange (SCE) rates and on human lymphocyte proliferation kinetics. The antitumor activity of these compounds was tested on leukemia P388- and leukemia L1210-bearing mice. The two chemicals in mixtures enhance SCE induction and antitumor activity in a synergistic manner. The homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenyl acetic acid was found to be more effective than the homo-aza-steroidal ester of o-bis(2-chloroethyl)aminobenzoic acid in causing cytogenetic damage and antineoplastic activity. A correlation was observed between the magnitude of the SCE response and the depression of the cell proliferation index. The order of the antitumor effectiveness of the five different treatments tested coincided with the order of the cytogenetic effects they induced.
Treatment of Malaria tropica with a Fixed Combination of Rifampicin, Co-Trimoxazole and Isoniazid: A Clinical Study
Authors: Goerg H. , Ochola S.A. , Goerg R.
Published: April 2003

The treatment of malaria tropica is becoming difficult because of the increasing drug resistance rates of Plasmodium falciparum against several of the currently available antimalarias. A fixed combination of rifampicin, co-trimoxazole and isoniazid (CotrifazidTM, CF) was found to be highly effective for the treatment of malaria tropica. The aim of the present study in Kenya was to scrutinize this finding in a 14-day trial. Patients with malaria tropica were given in an open, double-arm randomized study CF for 5 days, or chloroquine or pyrimethamine/sulphadoxine as the control. Because of an apparently better activity and tolerance of CF, the randomization had to be stopped after the enrollment of 50 patients. A total of 61 patients in both groups (35 of them between 2 months and 6 years of age) were available for final analysis. All 41 patients treated with CF, originally positive in their blood smears, turned negative; in 2 cases blood smear positivity reappeared on day 14. There were 7 failures in the control group, 4 of them a primary one. Four of those failures were turned negative with CF, 2 failed with CF also, and 1 disappeared. The tolerance of CF was excellent even in infants. In our experience, CF is very well suited for the treatment of malaria tropica, also in cases of apparent drug resistance of P. falciparum against other antimalarials, and even in severe cases of the disease.
Phase I Pharmacokinetic Study of a New 3-Azinomethyl-Rifamycin (Rifametane) as Compared to Rifampicin
Authors: Potkar C. , Gogtay N. , Gokhale P. , Kshirsagar N.A. , Ajay S. , Cooverji N.D. , Bruzzese T.
Published: April 2003

An open randomized cross-over study was conducted in 8 healthy male volunteers to study the pharmacokinetic pattern and the safety of a 300-mg single oral dose of a new 3-azinomethyl-rifamycin (USAN rifametane, SPA-S-565) compared with 300 mg of conventional rifampicin. The pharmacokinetic profiles of rifametane were significantly more favorable than those of rifampicin. The serum peak value was 7.82 µg/ml for rifametane and 4.04 µg/ml for rifampicin (p < 0.001); the elimination half-life was 10.58 h for rifametane and 1.89 h for rifampicin (p < 0.001); area under the serum concentration curve from 0 to infinity was 142.3 µg·h/ml for rifametane and 19.9 µg·h/ml for rifampicin (p < 0.001); the mean residence time was 18.05 h for rifametane and 3.93 h for rifampicin (p < 0.001). Rifametane showed a good safety profile after the 300-mg single oral dose. Three volunteers developed a mild headache, metallic taste and slightly elevated temperature for 3–4 h, which subsided without medication. Clinically or statistically significant changes in laboratory parameters were not found between baseline and posttreatment values.
Mechanisms of Action of Quinolones against Staphylococci and Relationship with Their in vitro Bactericidal Activity
Authors: Ramón M. Sales , Cantón Emilia , Pemán Javier , Pastor Amparo , Martínez José P.
Published: April 2003

Ciprofloxacin and norfloxacin exhibited mechanism A (requires cell division as well as bacterial protein and RNA synthesis to kill bacteria) and C (active against nondividing bacteria but requires protein and RNA synthesis) against the reference strain Staphylococcus aureus ATCC 25923, yet only mechanism A was exhibited by these fluoroquinolones when tested against three clinical isolates: S. aureus Sa-215, Staphylococcus epidermidis Se-81 and Staphylococcus haemolyticus Sx-1. On the contrary, fleroxacin exerted mechanism A and C against the three clinical isolates but only mechanism A against the reference strain. Ofloxacin displayed mechanism A against S. epidermidis Se-81, mechanism A and C against S. haemolyticus and mechanism A and B (active against nondividing bacteria and does not require protein and RNA synthesis) against the two S. aureus tested. Sparfloxacin showed mechanism A and C against the four Staphylococcus species studied, and temafloxacin was the only fluoroquinolone tested that exhibited mechanism A and B against the four bacterial strains assayed. No correlation was found between the in vitro bactericidal activity (expressed as minimum inhibitory concentration and optimal bactericidal concentration) and the mechanisms of action exhibited by these fluoroquinolones.
Low-Dose Amphotericin B Lipid Complex for the Treatment of Persistent Fever of Unknown Origin in Patients with Hematologic Malignancies and Prolonged Neutropenia
Authors: Martino Rodrigo , Subirá Maricel , Domingo-Albós Andreu , Sureda Anna , Brunet Salut , Sierra Jordi
Published: April 2003

We studied the safety of low-dose amphotericin B lipid complex (ABLC, at 1 mg/kg/day) in 30 persistently febrile (>38°C for at least 5 days or with recurrent fever after 3 days of apyrexia) and neutropenic (<0.5 × 109/l) adult patients with hematologic malignancies. The median age was 45 years (range 18–67), most (60%) had an acute leukemia and all had fever of unknown origin (FUO). The total duration of neutropenia was a median of 17 days (range 9–33), and the total number of days with fever 10 days (range 6–39). Seven patients experienced mild-to- moderate infusion-related adverse events (IRAE). The serum creatinine and urea increased from baseline to end of therapy in 76 and 63% of cases, but the maximum levels reached were <130 µmol/l and <11 mmol/l, respectively, in all cases. Liver enzymes showed modest but significant increases in most patients during therapy, while bilirubin decreased in 74% of cases. Response to treatment (defervescence within 6 days without developing a fungal or nonfungal infection) was seen in 22 cases (73%, 95% CI 58–89%), while 8 episodes were considered treatment failures: 2 due to persistent FUO, 1 withdrew due to IRAE, 2 developed nonfungal infections and 3 developed a presumed or definite invasive mycosis. We conclude that low-dose ABLC is very safe and well tolerated and seems as effective as c-AmB for this indication. Thus, randomized trials at this dose level appear justified to demonstrate any real benefit over c-AmB or other lipid formulations for the treatment of FUO in neutropenic patients.
Long-Acting versus Short-Acting Cephalosporins for Preoperative Prophylaxis in Breast Surgery:A Randomized Double-Blin d Trial Involving 1,766 Patients
Authors: Thomas R. , Alvino P. , Cortino G.R. , Accardo R. , Rinaldo M. , Pizzorusso M. , Cesareo E. , D’Aiuto G.
Published: April 2003

Postoperative infectious complications after breast surgery may result in significant morbidity, psychological trauma, and additional costs. We assessed the efficacy of preoperative antibiotic prophylaxis for surgery in a randomized, double-blind trial of 1,766 patients undergoing breast surgery. From January 1, 1996 to August 31, 1997, all eligible patients were assigned randomly to receive a single dose of ceftriaxone (2 g) or ceftazidime (2 g) given intravenously at the induction of anesthesia, with no further doses. The groups were similar with respect to age, operative procedure, operative time and time to discharge after operation. The patients who received ceftriaxone prophylaxis had 54.4% fewer overall infections than those who received ceftazidime prophylaxis. Wound infection occurred in 0.45% of the ceftriaxone recipients (2 of 883) and 0.91% of the ceftazidime recipients (8 of 883). This prospective randomized double-blind study showed that the long-acting regimen containing ceftriaxone is more cost-effective than the short-acting ceftazidime in preventing postoperative infections in patients subjected to breast surgery.
Killing of Gram-Negative Bacteria by Ciprofloxacin within both Healthy Human Neutrophils and Neutrophils with Inactivated O2-Dependent Bactericidal Mechanisms
Authors: Cantón E. , Peman J. , Cabrera E. , Velert M. , Orero A. , Pastor A. , Gobernado M.
Published: April 2003

The intraphagocytic killing of Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa, and Salmonella typhi by ciprofloxacin (0.1, 1 and 5 μg/ml) within human neutrophils with intact and impaired (by phenylbutazone treatment) O2-dependent killing mechanisms was studied and compared with the extracellular killing in the same medium of the intraphagocytic killing, but omitting neutrophils. The MIC/MBC of ciprofloxacin in vitro (assays performed according to NCCLS specifications) were: 0.015/0.06 for E. coli, 0.12/32 for S. marcescens, 1/16 for P. aeruginosa, and 0.007/0.06 for S. typhi. Ciprofloxacin showed bactericidal activity both extracellular and within phenylbutazone-treated and untreated neutrophils. The minimum concentration of ciprofloxacin to kill 90% of phagocytosed bacteria within neutrophils with normal O2-dependent killing power after 30 min was: 0.1 μg/ml for E. coli, and S. typhi, 1 μg/ml for P. aeruginosa, and 5 μg/ml for S. marcescens. In contrast, exposure for 60 min was required to reach this percentage within phenylbutazone treated neutrophils. The minimum concentration to kill 90% of extracellular bacteria after 30 min was: 0.1 μg/ml for E. coli, P. aeruginosa and S. typhi, and 5 μg/ml, for S. marcescens. A positive interaction between ciprofloxacin and the O2-dependent mechanisms of phagocytes was found. The reactive oxygen metabolites produced in the respiratory burst did not affect the intraphagocytic activity of ciprofloxacin. Phenylbutazone treatment of phagocytes would be a good experimental model to study the intraphagocytic killing of drugs in situations such as AIDS and chronic granulomatous disease where inefficient oxidative mechanisms of neutrophils exist.
Ionic Binding of 3H-Gentamicin and Short-Time Bactericidal Activity of Gentamicin against Pseudomonas aeruginosa Isolates with Different Lipopolysaccharide Structures
Authors: Saika Takeshi , Hasegawa Miyuki , Kobayashi Intetsu , Nishida Minoru
Published: April 2003

The clinical isolates of Pseudomonas aeruginosa can be roughly classified into long- and short-LPS strains and LPS-deficient strains. Ionic binding of 3H-gentamicin was the highest in the long-LPS strains followed in descending order by short-LPS and LPS-deficient strains. However, PAC605 strain, completely lacking in the repeated units of O-polysaccharide and also lacking in some of the neutral sugar residues of the core oligosaccharide region, highly bound to 3H-gentamicin and it is suggested that the negatively charged sites on the deep-core oligosaccharide region and/or on lipid A participated in the binding to 3H-gentamicin. This manner of binding may be also applied to P. aeruginosa No. 45 (LPS-deficient), a clinical isolate.
An Adverse Interaction between Warfarin and 5-Fluorouracil: A Case Report and Review of the Literature
Authors: Brown Michael C.
Published: April 2003

Adverse interactions between warfarin and 5-fluorouracil (5-FU) have been reported. Such an interaction occurred in a patient with lung cancer receiving vinblastine and 5-FU. This case is the first involving a patient taking minidose warfarin for prophylaxis of catheter-associated thrombosis. Although the mechanism of the interaction is unclear, it has been postulated that 5-FU interferes with the synthesis of hepatic cytochrome P-450 2C9. Because warfarin and 5-FU are regularly coadministered, this adverse interaction might be occurring more frequently than is realized. Clinicians should be aware of this interaction and should regularly monitor the prothrombin time of patients receiving warfarin and 5-FU.
Adequate Macrolide Treatment Schedules for Uterine Cervicitis Caused by Chlamydia trachomatis
Authors: Mikamo Hiroshige , Sato Yasumasa , Hayasaki Yoh , Tamaya Teruhiko
Published: April 2003

To evaluate in vivo efficacy of macrolides; erythromycin (EM) and clarithromycin (CAM), in the different treatment schedules of Chlamydia trachomatis uterine cervicitis im women. Cervical C. trachomatis was detected by the polymerase chain reaction. EM was orally administered to 8, 15 and 18 Japanese patients, at a dosage of 600 mg, t.i.d. for 5, 7 and 14 days, respectively. CAM was orally administered to 10, 26 and 19 Japanese patients at a dosage of 400 mg, b.i.d. for 5, 7 and 14 days, respectively. The eradication rate and the recurrence rate in the different treatment schedules of C. trachomatis were evaluated. The eradication rates after 5, 7 or 14 days of treatment with EM were 1/8, 8/15 or 13/18, respectively. The recurrence rates after 5, 7 or 14 days of treatment with EM were 1/1, 3/8 or 2/13, respectively. On the other hand, the eradication rates after 5, 7 or 14 days of treatment with CAM were 5/10, 26/26 or 19/19, respectively. The recurrence rates after 5, 7 or 14 days of treatment with CAM were 3/5, 0/26 or 0/19, respectively. A 7-day treatment with CAM would be adequate and effective for C. trachomatis uterine cervicitis.
Interactions of Antineoplastic Chemotherapy with Zidovudine Pharmacokinetics in Patients with HIV-Related Neoplasms
Authors: Toffoli Giuseppe , Errante Domenico , Corona Giuseppe , Vaccher Emanuela , Bertola Antonella , Robieux Isabel , Aita Paola , Sorio Roberto , Tirelli Umberto , Boiocchi Mauro
Published: April 2003

To evaluate the perturbations in zidovudine (ZDV) pharmacokinetics as a consequence of antineoplastic chemotherapeutic treatments, we performed a prospective crossover study in 13 HIV-infected patients with cancer. The subjects received 2-day regimens of ZDV (250 mg × 2/day). On the first day ZDV was administered alone, whereas on the second day it was combined with antitumor chemotherapies specific for the histological type (ZDV + chemotherapy). Blood sample and urine collections were performed over a 12-hour period following oral administration of the antiretroviral agent. ZDV was measured with high-performance liquid chromatography. Pharmacokinetic parameters of ZDV were calculated by a noncompartmental model. The mean ZDV area under curve (AUC) was not significantly different in the patients treated with ZDV alone and ZDV + chemotherapy. Comparison of plasma elimination half-life (t½), apparent systemic clearance (CL/F), and apparent volume of distribution (Vd/F) of ZDV did not show any significant difference before and after chemotherapy. Conversely, some significant differences were observed for both mean peak concentration (Cmax) of ZDV and the corresponding time (Tmax). There was a 57% reduction in Cmax (p < 0.05) and a 66% increase in Tmax (p < 0.05) after chemotherapy compared with treatment with ZDV alone. No differences were observed in the urinary excretion of ZDV and ZDV glucuronide and urinary metabolic ratio, as a consequence of antineoplastic treatment. In conclusion, this study demonstrates that some minor perturbations in ZDV pharmacokinetics (i.e. Cmax and Tmax) derived from antineoplastic chemotherapy. Based on the observation that antineoplastic chemotherapy had no significant effect on plasma ZDV concentration expressed as AUC, the observed pharmacokinetic interaction would not warrant by itself a change in the ZDV dosage during chemotherapy.
Cellular Effects of Olomoucine in Human Lymphoma Cells Differing in p53 Function
Authors: Fan Saijun , Duba Diane E. , O’Connor Patrick M.
Published: April 2003

Olomoucine, a purine derivative, inhibits multiple cyclin-dependent kinases that play important roles in regulating the G1/S and G2/M transitions of the cell cycle. In this study we investigated the cellular effects of olomoucine in two human Burkitt’s lymphoma cell lines, WMN (containing wild-type p53) and CA46 (containing mutant p53), and found that in consistency with its ability to block the activity of cyclin E/Cdk2 and cyclin B1/Cdc2 kinases, olomoucine caused cell cycle arrest at both G1/S and G2/S boundaries. Moreover, cell cycle arrest occurred equally well in these two cell lines bearing different p53 gene status, suggesting that p53 was not responsible for the cell cycle arrest by olomoucine. A similar p53-independent fashion was also observed in the cytotoxic potency and apoptosis induction of olomoucine, in contrast to ionizing radiation which caused more cytotoxic activity and apoptosis in the WMN cell line bearing wild-type p53 compared with CA46 cells bearing mutant p53. Such p53-independent cytotoxicity of olomoucine was also confirmed in other human Burkitt’s lymphoma and lymphoid cell lines containing wild-type and mutant p53. Therefore, our results give an impetus to continued research into olomoucine that might be a very useful chemotherapeutic strategy in the treatment of patients with mutant p53 tumors, at least in lymphoma patients.
Quantitative Assessment of Malaysian Plasmodium falciparum Clones to Schizontocidal Drugs before and after Cryopreservation
Authors: Ang Hooi Hoon , Cheang Hung Seong
Published: April 2003

Thirty clones were obtained from five Malaysian Plasmodium falciparum isolates using the limiting dilution method. These clones were then subjected to antimalarial testing using the modified in vitro microtechnique. The results showed that ST 85/B3, GC/C10 and ST 85/A2 clones decreased their susceptibilities to 19, 41 and 28% whilst ST 12/F8, ST 85/B3 and ST 85/B3 clones showed increases of 6, 43 and 21%, respectively, against chloroquine, mefloquine and quinine after cryopreservation. Further results also indicated that GC/B4, GC/B7, GC/C10, ST 85/A5, ST 85/D3, ST 148/F8 clones did not show any change (up to 2 decimal places) against chloroquine, ST 12/D5, ST 12/E8, ST 12/F8, ST 148/A5 clones against quinine after cryopreservation. They, however, maintained their original susceptibilities after cryopreservation.
Isoniazid plus Sulphadoxine-Pyrimethamine Can Reduce Morbidity of HIV-Positive Patients Treated for Tuberculosis in Africa: A Controlled Clinical Trial
Authors: Haller Louis , Sossouhounto Raoul , Coulibaly Issa M. , Dosso Mireille , Kone Moussa , Adom Hilaire , Meyer Urs A. , Betschart Bruno , Wenk Markus , Haefeli Walter E. , Lobognon Legré R. , Porquet Michel , Kaboré Geneviève , Sorenson Fred , Reber-Liske Rosemaria , Stürchler Dieter
Published: April 2003

An annual 20% excess mortality rate is observed in HIV-seropositive patients after treatment for tuberculosis. An affordable secondary prophylaxis against main opportunistic diseases is needed, i.e. against tuberculosis, toxoplasmosis, pneumocystosis and other infections occurring in this target population. This open prospective randomized study assessed morbidity and mortality in 2 cohorts of HIV-seropositive patients having recently recovered from pulmonary tuberculosis: 134 patients assigned to prophylactic treatment with isoniazid (INH, 300 mg once daily) plus sulphadoxine-pyrimethamine (S, 500 mg/P, 25 mg once weekly), and 129 were controls, comparable for sex, age, weight and HIV-serology. Patients were followed-up for up to 2 years: 192 person-years (PY) in the prophylaxis group and 142 PY in the control group. Four patients developed tuberculosis and 20 patients died in the prophylaxis group, compared to 10 and 23 controls, respectively. Sick days were reported by 22 patients in the prophylaxis group and by 77 patients in the control group. This prophylaxis was associated with a moderate decrease of mortality (log rank test: p = 0.1736), a significant decrease of tuberculosis incidence (log rank test: p = 0.0234), a highly significant reduction of adverse events and sick days, and a prevention of wasting (p = 0.008) and anaemia (p = 0.045). No death from toxoplasmosis occurred in the prophylaxis group as compared to 2 possible cases among controls; toxoplasmosis IgG levels declined in treated patients, but increased in controls (p = 0.01). There was no adverse drug reaction due to SP (10,006 doses) or to INH. Compliance with SP intake was good, but moderate as with INH intake. We conclude that a secondary prophylaxis with INH+SP represents a cost-effective measure to improve health conditions of HIV-infected adults in Côte d’Ivoire, following a full treatment course against tuberculosis.
Lack of Effect of Gemifloxacin on the Steady-State Pharmacokinetics of Theophylline in Healthy Volunteers
Authors: Davy Maria , Allen Ann , Bird Nicholas , Rost Karl Ludwig , Fuder Hermann
Published: April 2003

Gemifloxacin is a novel fluoroquinolone, currently in development for the treatment of respiratory tract infections. This double-blind (with respect to gemifloxacin), randomized, crossover study investigated the possibility of pharmacokinetic interaction between gemifloxacin and theophylline. After a 4–8-day run-in phase to establish the dose of theophylline required to achieve a trough plasma concentration range of 8–15 mg/l, 15 healthy volunteers entered a randomized treatment phase. Volunteers then received oral theophylline, 300–400 mg twice daily, for 22 days. On days 5–11 and 16–22, they also received either placebo or gemifloxacin, 320 mg p.o. once daily, in a crossover fashion. Blood samples were collected up to 12 h after the morning dose of theophylline on days 11 and 22. Theophylline pharmacokinetics were not affected by the co-administration of gemifloxacin. The maximum plasma concentration (Cmax) for theophylline ranged from 8.12 to 17.71 mg/l and from 8.79 to 16.35 mg/l during concomitant administration with gemifloxacin and placebo, respectively. The corresponding ranges of the area under the plasma concentration-time curve from time zero to the last quantifiable plasma concentration (AUC(0–12)) were 84.6–177.5 mg·h/l and 94.8–165.1 mg·h/l during gemifloxacin and placebo administration, respectively. The point estimates (90% confidence intervals) for dose-normalized AUC(0–12) and Cmax (theophylline + gemifloxacin):(theophylline + placebo) were 0.99 (0.93, 1.05) and 1.02 (0.93, 1.11), respectively, which were entirely within the equivalence range (0.80, 1.25). The co-administration of gemifloxacin and theophylline was well tolerated, with no clinically significant changes seen in vital signs, 12-lead electrocardiogram readings or laboratory parameters. Adverse events were generally transient, mild to moderate in nature and similar during the gemifloxacin and placebo treatment periods. In conclusion, theophylline and gemifloxacin may be co-administered without any adjustment in theophylline dose.
Effect of Maalox® on the Bioavailability of Oral Gemifloxacin in Healthy Volunteers
Authors: Allen Ann , Vousden Marika , Porter Angela , Lewis Anastasia
Published: April 2003

This open, randomized, 4-way crossover study investigated the effect of the antacid Maalox® on the bioavailability of gemifloxacin, a novel fluoroquinolone antimicrobial. Sixteen healthy male volunteers received gemifloxacin, 320 mg p.o., alone, 3 h after Maalox® administration, or 10 min or 2 h before Maalox® administration. Blood was sampled for 48 h after dosing to determine pharmacokinetic parameters. Estimates for the differences between regimens and 95% confidence intervals were calculated using the t-test for paired data. The administration of gemifloxacin 10 min before Maalox® resulted in an average 85% reduction in the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0–∞), whereas administration 3 h after Maalox® produced a decrease in AUC0–∞, 15% of which was not considered to be clinically significant. The administration of gemifloxacin 2 h before Maalox® had no notable effect on the gemifloxacin AUC0–∞ (average increase of 3%). Similar results were seen for the maximum gemifloxacin plasma concentration (Cmax). Neither the time to Cmax nor the half-life of gemifloxacin were notably altered by the administration of Maalox® at any time relative to gemifloxacin dosing. There were no clinically important adverse experiences or changes in clinical laboratory parameters during this study. The findings of this study support the dosing recommendation that gemifloxacin can be administered either 2 h or more prior to, or 3 h or more after, the administration of Maalox®.
In vitro Activity of Moxifloxacin Compared to Other Fluoroquinolones against Different Erythromycin-Resistant Phenotypes of Group A β-hemolytic Streptococcus
Authors: Esposito Silvano , Noviello Silvana , Ianniello Filomena , Novelli Andrea
Published: April 2003

The aim of the present study was to evaluate the in vitro activity of moxifloxacin (BAY 12–8039) compared to ciprofloxacin, ofloxacin and sparfloxacin against 156 group A β-hemolytic Streptococcus strains. Sixty strains were macrolide-, lincosamide- and streptogramin-B-susceptible; 16 strains exhibited a constitutive resistance phenotype; 32 strains exhibited an inducible phenotype, and 48 strains were characterized by the M-type efflux-dependent phenotype. The minimum inhibition concentrations were determined by an agar dilution method according to NCCLS-approved guidelines. Moxifloxacin showed an enhanced activity compared with the other fluoroquinolones against the different macrolide-resistant phenotypes.
In vitro Investigation of the Antimicrobial Activities of Novel Tetramethylpiperidine- Substituted Phenazines against Mycobacterium tuberculosis
Authors: van Rensburg Constance E.J. , Jooné Gisela K. , Sirgel Frederick A. , Matlola Nthane M. , O’Sullivan John F.
Published: April 2003

The intra- and extracellular activities of 5 novel tetramethylpiperidine (TMP)-substituted phenazines against Mycobacterium tuberculosis H37Rv (ATCC 27294) were determined and compared with those of clofazimine and rifampicin. Two of these agents, together with clofazimine, were also tested for their activities against drug-resistant strains of M. tuberculosis. Three of the TMP-substituted phenazine compounds were significantly more active than clofazimine against M. tuberculosis, including multidrug-resistant clinical strains of this microbial pathogen, demonstrating a lack of cross-resistance between the riminophenazines and standard anti-tuberculous drugs. Using M. tuberculosis-infected monocyte-derived macrophages, all of the TMP-substituted phenazines were found to possess intracellular activity which was superior to that of both clofazimine and rifampicin. In this model of intracellular bioactivity, the experimental compounds inhibited bacterial growth at concentrations which were approximately 10-fold lower than the corresponding minimal inhibitory concentration values obtained using conventional in vitro sensitivity testing procedures. These results demonstrate that the novel TMP phenazines are active against multidrug-resistant M. tuberculosis strains, and particularly effective intracellularly.
In vitro and in vivo Antibacterial Activities of Biapenem in the Fields of Obstetrics and Gynecology
Authors: Mikamo Hiroshige , Sato Yasumasa , Hayasaki Yoh , Tamaya Teruhiko
Published: April 2003

Biapenem is a new injectable carbapenem antibiotic which has favorable pharmacokinetic properties, and is stable to hydrolysis by dehydropeptidase I. Biapenem inhibited more than 90% of clinical isolates of Streptococcus agalactiae, Escherichia coli, Peptostreptococcus magnus, Bacteroides fragilis and Prevotella bivia at the concentration of 3.13 mg/l. The MIC90 of biapenem against Pseudomonas aeruginosa was lower than that of panipenem, equivalent to that of imipenem, and greater than that of meropenem. The in vivo efficacy of biapenem was evaluated using the experimental infection model of uterine endometritis. The accumulation of neutrophils in the uterus in the biapenem- treated group was less marked than in the nontreated group, as well as bacteriological response. These results suggest that the new antimicrobial agent biapenem might be useful for the treatment of polymicrobial infections in the fields of obstetrics and gynecology.
Bactericidal Activity of Gatifloxacin (AM-1155) against Pseudomonas aeruginosa and Enterococcus faecalis in an in vitro Bladder Model Simulating Human Urinary Concentrations after Oral Administration
Authors: Takahashi Satoshi , Ebisu Hiroyuki , Hirose Takaoki , Sano Masato , Nishimura Masahiro , Hirai Keiji , Tsukamoto Taiji , Hosaka Masaki
Published: April 2003

The bactericidal activity of gatifloxacin, a new 6-fluoro-8-methoxy quinolone, was determined in a dynamic in vitro model mimicking complicated lower urinary tract infection. Strains of  Pseudomonas aeruginosa and Enterococcus faecalis with different susceptibility were exposed to changing gatifloxacin concentrations, simulating human urinary concentrations afer oral treatment with 200 mg twice daily for 3 consecutive days. Bacterial numbers of P. aeruginosa (minimal inhibitory concentrations, MIC: ≤ 32 μg/ml) and of E. faecalis (MIC: 16 μg/ml) were reduced to undetectable levels during exposure. For the strains with lower susceptibility, gatifloxacin showed bactericidal activity, but eradication was not complete. Thus, in a complicated urinary tract infection model, breakpoint MICs of gatifloxacin for uropathogenic organisms were presumed to range from 16 to 32 μg/ml. At least 86% of recent clinical isolates of P. aeruginosa and E. faecalis were inhibited at its breakpoint MIC. These results suggest that gatifloxacin may be useful in the treatment of urinary tract infections.
Effects of Antibiotics on Adherence of Pseudomonas aeruginosa and Pseudomonas fluorescens to A549 Pneumocyte Cells
Authors: Di Martino Patrick , Rebière-Huët Julie , Hulen Christian
Published: April 2003

The aim of this study was to evaluate the effect of antibiotics at subminimal inhibitory concentrations (sub-MIC) on fluorescent pseudomonas adherence to A549 pneumocyte cells. Pseudomonas fluorescens MF0 isolated from contaminated raw milk and Pseudomonas aeruginosa NK125502 isolated from a cystic fibrosis patient’s lung adhered to A549 cells. As previously shown for P. aeruginosa, P. fluorescens bound to A549 cells in a dose-dependent manner over a wide range of bacterial concentrations. Bacterial growth in the presence of polymyxin B or gentamicin at MIC/2 had no effect on the adherence of NK125502 and MF0 to A549 cells. Instead, MIC/2 and MIC/8 of cefsulodin or chloramphenicol decreased the adherence of the two strains. A decrease in MF0 adherence was also observed with cefsulodin at MIC/32. We conclude that, in addition to their antibacterial activity, cefsulodin and chloramphenicol could be effective in preventing Pseudomonas adherence to respiratory epithelium.
Adequate Levofloxacin Treatment Schedules for Uterine Cervicitis Caused by Chlamydia trachomatis
Authors: Mikamo Hiroshige , Sato Yasumasa , Hayasaki Yoh , Hua Yin Xiang , Tamaya Teruhiko
Published: April 2003

The in vivo efficacy of levofloxacin (LVFX), one of the most standard new quinolone antimicrobial agents, in the different treatment schedules of Chlamydia trachomatis uterine cervicitis in women was evaluated. Cervical C. trachomatis was detected by polymerase chain reaction. LVFX at a dosage of 300 mg t.i.d. for 5, 7 and 14 days was orally administered to 18, 33 and 35 Japanese patients, respectively. The eradication rate and the recurrence rate in the different treatment schedules of C. trachomatis were evaluated. The eradication rate in 5-, 7- or 14-day cases was 44.4, 87.9 or 88.6%, respectively. The recurrence rate of 5-, 7- or 14-day cases was 50.0, 0 or 0%, respectively. Seven-day treatment with LVFX is adequate for and effective in C. trachomatis uterine cervicitis.
Influence of Temperature and Concentration on the Postantifungal Effect and the Effects of Sub-MIC Concentrations of Four Antifungal Agents on Previously Treated Candida Species
Authors: García M.T. , Llorente M.T. , Mínguez F. , Prieto J.
Published: April 2003

Background: The objective of this study was to investigate the impact of different temperatures (22, 35 and 37°C) on the postantifungal effect (PAFE) and the effect of sub-MIC concentrations (1/4 × MIC) on Candida albicans and Candida glabrata in PAFE stage (PAFSE). Methods: This stage was induced by a 1.5-hour pretreatment with different doses (1 ×, 4 × and 8 × MIC) of four antifungal agents that are fundamental to modern candidiasis therapy. Results: The temperature, as well as the dose of the antifungal agent that was applied during the pretreatment, determined the duration of the two studied effects. An increase in the temperature and/or the dose prolonged the duration of the PAFE and PAFSE in both species, independent of the applied antifungal agent. Amphotericin B and 5-fluorocytosine always induced significant PAFEs (0.5–4.8 h and 0.5–3.0 h, respectively), which were increased (0.7–3.4 h and 0.5–3.2 h, respectively) by posterior exposure to 1/4 × MIC of the respective antifungal agent. In the case of ketoconazole and fluconazole, temperature and concentration were especially important. Although neither antimycotics was able to induce a significant PAFE, posterior exposure to 1/4 × MIC of each of the two azoles led in both yeast species to a significant PAFSE of up to 0.8 h (if the concentrations and/or the temperatures were high enough). Conclusion: Factors such as temperature and concentration could be important when choosing an antifungal agent.
In vitro Activity of Rifaximin, Metronidazole and Vancomycin against Clostridium difficile and the Rate of Selection of Spontaneously Resistant Mutants against Representative Anaerobic and Aerobic Bacteria, Including Ammonia-Producing Species
Authors: Marchese Anna , Salerno Angelo , Pesce Adelaide , Debbia Eugenio A. , Schito Gian Carlo
Published: April 2003

Background: Rifaximin is a rifamycin derivative characterized by a wide antibacterial activity. This drug is neither absorbed by the gastrointestinal tract nor inactivated by gastric juices, and exerts its action entirely within the intestinal lumen. Methods: In this study, the activity of this antibiotic was compared with that of metronidazole and vancomycin against 93 Clostridium difficile isolates. The rate of emergence of bacteria spontaneously resistant to the new compound was also evaluated in relation to representative gram-positive and gram-negative strains. In terms of MIC50 values, rifaximin showed an intrinsic activity superior to that of the other agents. The emergence of spontaneously resistant strains was assessed with 46 aerobic (staphylococci, enterococci, Proteus spp., Citrobacter freundii, Providencia rettgeri, enteropathogenic, enteroinvasive, enterotoxigenic and entero- hemorrhagic Escherichia coli, and Salmonella enteritidis) and anaerobic (Clostridium spp., Bacteroides spp., Fusobacterium nucleatum and Peptococcus spp.) pathogens, most of them also ammonium producers. Two different methods, broth and agar dilution, were employed. Results: When liquid medium was employed, bacteria capable of sustained growth in 100 μg/ml of rifaximin were obtained after 2–5 transfers with gram-positive aerobic cocci, 2–3 transfers with gram-negative aerobic strains and 2–5 transfers with anaerobic species. At the highest dose used with the agar dilution method (8 × MIC), the frequency of emergence of spontaneously resistant mutants ranged from <1 × 10–9 to 1.6 × 10–8 with gram-positive aerobic and anaerobic cocci, while with aerobic and anaerobic gram-negative bacteria, this value ranged from <1 × 10–9 to 1.7 × 10–7. C. difficile showed a particularly low incidence of spontaneously resistant mutants (<1 × 10–9). The low incidence of resistant subpopulations selected by levels of 8 × MIC of rifaximin suggests that the high levels of the drug which were reached in the gastrointestinal lumen may further prevent the selection of mutants. Conclusion: The low toxicity, broad antibacterial activity and very poor absorption from the gastrointestinal tract of rifaximin suggest a potential therapeutic use for this drug in gastrointestinal diseases, as well as in the management of patients with cirrhosis and chronic portal-systemic encephalopathy.
Comparative Effect of Thiamphenicol Glycinate, Thiamphenicol Glycinate N-Acetylcysteinate, Amoxicillin plus Clavulanic Acid, Ceftriaxone and Clarithromycin on Pulmonary Clearance of Haemophilus influenzae in an Animal Model
Authors: Drago Lorenzo , Fassina Maria Cristina , Mombelli Barbara , De Vecchi Elena , Lombardi Alessandra , Gismondo Maria Rita
Published: April 2003

Background: Thiamphenicol glycinate (TG) and its derivative thiamphenicol glycinate N-acetylcysteinate (TGA) could be a valid therapeutic option in the treatment of respiratory tract infections. Methods: Time-kill curves of TG and TGA and pulmonary clearance in Haemophilus influenzae infected guinea pigs were compared with those of clarithromycin, ceftriaxone and amoxicillin plus clavulanic acid. Results: The bacterial activities of the tested antibiotics were comparable. When compared to the control group, lung bacterial counts were significantly lower for the TGA group at 3 h vs. controls, while for the other treatments, significant decreases were recorded after 6 h. All drugs showed a log count of <2.0 at 24 h with respect to the control while at 48 h all groups demonstrated a log count of <2.0. Conclusions: Although the in vitro activity of the tested drugs evaluated by time-kill curves seemed comparable, some pharmacokinetic and pharmacodynamic characteristics of TGA contribute to improving the resolution of the infective process.
Intensive Intravenous Amphotericin B for Prophylaxis of Systemic Fungal Infections
Authors: Karthaus M. , Doellmann T. , Klimasch T. , Elser C. , Rosenthal C. , Ganser A. , Heil G.
Published: April 2003

Background: Invasive fungal infections are an increasing cause of morbidity in acute leukemia (AL) patients. Methods: In a prospective pilot trial, the safety and efficacy of antifungal prophylaxis with intravenous (i.v.) amphotericin B (AMB; 1 mg/kg every 48 h) was studied in 46 consecutive cycles. Prophylaxis with i.v. AMB was carried out in patients treated with intensive chemotherapy for AL and compared with a control of 49 cycles without prophylaxis. Results: Pulmonary infiltrates (5 vs. 23; p < 0.001) and fungal microabscesses in the liver or spleen (0 vs. 6; p = 0.014) occurred significantly less frequently in the prophylaxis group. While there were 3 deaths related to systemic fungal infections in the control group, there were none in the prophylaxis group. Escalation to conventional AMB (1.0 mg/kg/day) was significantly less frequent in the prophylaxis group (9 out of 46 cycles) compared with the control arm (29 out of 49 cycles; p = 0.001). A total of 695 mg of AMB per cycle was administered in the prophylaxis arm, compared with 634 mg/cycle for empirical treatment in the control group (p = 0.6). Infusion-related toxicity was documented in 29% of the cycles of prophylaxis compared with 55% of the cycles of empirical treatment with i.v. AMB in the control group. The nephrotoxicity of AMB prophylaxis was moderate, with ≥ WHO degree II reported in 1 out of 46 cycles only. Conclusion: Intensive i.v. AMB prophylaxis reduced invasive fungal infections and led to a reduction in fungal microabscesses in the liver or spleen, as well as pulmonary infiltrates, in patients treated for AL. The need for escalation to empirical i.v. AMB treatment was significantly reduced. Intensive AMB prophylaxis was feasible, with moderate adverse effects.
In vitro Susceptibility of Candida dubliniensis to Current and New Antifungal Agents
Authors: Quindós Guillermo , Carrillo-Muñoz Alfonso Javier , Arévalo María Pilar , Salgado Javier , Alonso-Vargas Rocío , Rodrigo José Manuel , Ruesga María Teresa , Valverde Anastasio , Pemán Javier , Cantón Emilia , Martín-Mazuelos Estrella , Pontón José
Published: April 2003

Background: Candida dubliniensis is a recently described Candida species closely related to Candida albicans, which has been associated with oral candidiasis in HIV-infected patients. Fluconazole-resistant strains of C. dubliniensis are easily obtained in vitro and this fact could be a complication if this resistance develops during treatment with this drug. Methods: In the present study, the in vitro antifungal susceptibilities of 36 C. dubliniensis clinical isolates and culture strains to current and new antifungal agents, such as amphotericin B (AMB), amphotericin B lipid complex (ABLC), amphotericin B colloidal dispersion (ABCD), 5-fluorocytosine (5FC), fluconazole (FLC), itraconazole (ITC), ketoconazole (KTC), liposomal amphoteri- cin B (LAMB), liposomal nystatin (LNYT), LY303366 (LY), SCH56592 (SCH), and voriconazole (VRC), were determined according to the National Committee for Clinical Laboratory Standards M27-A broth microdilution method for yeasts. Results: Most isolates of C. dubliniensis were susceptible to both new and current antifungal drugs, with 75.9% isolates susceptible to KTC, 86.2% to FLC and to ITC, and ∼100% to the other antifungal agents tested. The cross-resistance phenotypes are detailed. Four isolates were resistant (MIC ≥64 μg/ml) to FLC. These 4 isolates were also resistant to KTC, and 3 of them were also resistant to ITC (MIC ≥1 μg/ml for both agents). However, these isolates were highly susceptible to 5FC and all polyene formulations (AMB, ABLC, ABCD, LAMB, and LNYT), triazole (SCH and VRC) and echinocandin (LY) antifungal agents. Conclusion: The new liposomal and lipidic formulations of AMB, LNYT, and the new triazoles and echinocandins may provide new alternatives to FLC for the treatment of infections by C. dubliniensis.
In vitro Analysis of the Change in Resistance of Chlamydia trachomatis under Exposure to sub-MIC Levofloxacin for a Therapeutic Term
Authors: Takahashi Satoshi , Hagiwara Toshikatsu , Shiga Sadashi , Hirose Takaoki , Tsukamoto Taiji
Published: April 2003

Background: While fluoroquinolone-resistant Chlamydia trachomatis strains have not been clinically isolated, they were isolated in an in vitro study recently. Methods: To determine whether C. trachomatis strains develop resistance under sub-MIC antibacterial exposure in a clinical therapeutic term, C. trachomatis strains were exposed to sub-MIC levofloxacin (LVFX) for about 2 weeks. The MIC of LVFX was measured and DNA fingerprinting was performed every 72 h by PCR using random primers. Results: There was almost no change in the MIC under exposure to 0.125 μg/ml LVFX. However, some mutational changes in DNA fingerprints developed. Conclusions: In clinical therapeutic terms, resistant strains of C. trachomatis will probably not develop, even if sub-MIC LVFX is employed.
Helicobacter pylori Stimulates DNA Synthesis in a Small Intestinal Cell Line in vitro
Authors: Brännström Johanna , Zachrisson Kristina , Hultén Kristina , Engstrand Lars , Uribe Andrés
Published: April 2003

Background: Helicobacter pylori, which causes gastritis and peptic ulcer, seems to be an important factor in the pathogenesis of gastric cancer and MALT lymphoma. Thus our aim was to examine whether H. pylori influences DNA synthesis in epithelial cells in vitro. Methods: Sonicated and water extracts of H. pylori (cytotoxic strains NCTC 11637, 88-23 and A5, and a noncytotoxic isogenic mutant of A5, A5 vac A) were diluted to a final concentration of 1/1,000, 1/100, 1/50 and 1/10. Water extracts of Escherichia coli were used as reference. IEC-6 cells were incubated during 24 h with fragments of H. pylori or extracts of the concentrations described above. The cells were labeled with 3H-methylthymidine for 4 h and processed for autoradiography. DNA synthesis was evaluated by the labeling index (LI). Results: The LI% of controls was 15.6 ± 5.1%. All the water extracts and sonicated strains of H. pylori increased the LI% in a dose-dependent manner (p < 0.001). The highest concentrations of the sonicated strains tended to reduce the LI%, although these values were still higher than those of the control group. The water extracts of E. coli increased the LI% in a dose-dependent manner (p < 0.0001). Conclusion: H. pylori stimulates DNA synthesis in epithelial cells in vitro, but no association was found with the presence of cytotoxin production. Our results suggest that hitherto unknown components of H. pylori may contribute to the increase in cell proliferation observed in gastritis and to the development of MALT lymphoma and gastric cancer.
Spectrum of Cytokine Gene Expression in Intestinal Mucosal Lesions of Crohn’s Disease and Ulcerative Colitis
Authors: Funakoshi K. , Sugimura K. , Anezaki K. , Bannai H. , Ishizuka K. , Asakura H.
Published: April 2003

Background/Aims: We investigated the mRNA expression of spectrum of cytokines in the colonic mucosa in inflammatory bowel disease (IBD). Methods: The expression of cytokine gene was evaluated by using the reverse transcription-polymerase chain reaction and the radioactivity of amplified cDNA standardized by coamplified β-actin cDNA. Results: Crohn’s disease and ulcerative colitis showed significantly increased expression of IL-1β, IL-6, IL-8 and TNF-α mRNA as compared with controls (p < 0.05). Conclusion: Proinflammatory cytokines such as IL-1β, IL-6, IL-8 and TNF-α are closely involved in the immune abnormalities of inflammatory mucosal lesions in IBD.
Sexual Dysfunction in Patients with Irritable Bowel Syndrome and Non-Ulcer Dyspepsia
Authors: Fass R. , Fullerton S. , Naliboff B. , Hirsh T. , Mayer E.A.
Published: April 2003

The prevalence and type of sexual dysfunction in patients with functional gastrointestinal (GI) disorders involving the upper (functional dyspepsia) or lower GI tract (irritable bowel syndrome) were studied in 683 patients seen at a tertiary referral center and a comparison group of 247 community volunteers. Associations between sexual dysfunction and type and severity of GI symptoms, and psychological symptoms were examined. All subjects were evaluated with a validated bowel syndrome questionnaire, which included questions about sexual function. Psychological symptom severity was assessed by SCL-90R. The prevalence of self-reported sexual dysfunction in patients with functional GI disorders was 43.3% and did not differ by gender, age stratification or disease subtype: irritable bowel syndrome (IBS); non-ulcer dyspepsia (NUD), and IBS+NUD. In the comparison subjects without IBS symptoms and those with IBS symptoms but not seeking health care (IBS non-patients), the reported sexual dysfunction prevalence was significantly lower (16.1 and 24.4%, respectively, p < 0.005). Decreased sexual drive was the symptom most commonly reported by both male (36.2%) and female (28.4%) patients. Dyspareunia was reported by 16.4% of females and 4% of males with IBS, but was rarely observed in patients with NUD. Report of sexual dysfunction was positively associated with perceived GI symptom severity, but not with psychological symptom severity. Sexual dysfunction should be incorporated into the quality-of- life assessment of patients with functional GI disorders and addressed in future outcome studies.