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Biomedical subjects

I Shalit

Publications and source records attributed to I Shalit.

At least 19 recordsLinked to original sources

The inhibitory effect of ciprofloxacin on proliferation of a murine bladder carcinoma cell line.

Ciprofloxacin was tested for its effect on proliferation of a bladder carcinoma cell line, Jurkat T-cell leukaemia cell line and a normal human foreskin derived from a fibroblast cell line. Cell proliferation was measured by MTT tetrazolium salt colorimetric assay. Proliferation of bladder carcinoma cells was inhibited by ciprofloxacin in a dose and time dependent fashion. Initial inhibition was observed at a concentration of 25 mg/L (approximately 35% inhibition; P greater than 0.01) while 250 mg/L of ciprofloxacin, a concentration achievable in urine following conventional oral treatment, exerted a lytic effect on these cells. A maximum suppressive effect on cell proliferation was reached within the first 24 h of ciprofloxacin addition to cell cultures. The rate of reversal of the inhibition of proliferation was dependent on the initial drug concentration. Exposure of bladder carcinoma cell cultures to 250 mg/L ciprofloxacin resulted in irreversible inhibition of proliferation. Similar results were obtained for the fibroblast cell line and Jurkat T-cell line. The latter being slightly more sensitive towards ciprofloxacin treatment in vitro.

Animals

Augmentation of the antibacterial activity of magainin by positive-charge chain extension.

Novel analogs of the broad-spectrum antimicrobial peptide magainin-2 were obtained by extension of its chain through addition of segments of positively charged amino acids to either its N or its C terminus and by increasing its helicity. The activity of magainin-2 toward American Type Culture Collection strains of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus was most considerably enhanced by these modifications, whereas, in general, its low hemolytic capacity was not or was only slightly affected. The antibacterial potencies of magainin-2 and its derivatives were more evident following decreases of pH from 7.2 to 6 and 5.

Amino Acid Sequence

Enhanced repopulation of murine hematopoietic organs in sublethally irradiated mice after treatment with ciprofloxacin.

We analyzed the effect of ciprofloxacin, fleroxacin, and ceftazidime on production of colony-stimulating factors (CSF) by cultured murine spleen cells in the presence of pokeweed mitogen (PWM). Ciprofloxacin at concentrations of 5 to 10 micrograms/mL in concert with PWM stimulated CSF production by cultured spleen cells. A 3.5-fold increase in the number of CFU-C was observed in the presence of ciprofloxacin-PWM spleen conditioned medium (SCM) as compared with control cultures exposed to PWM-SCM only. Antimurine GM-CSF and antimurine interleukin-3 (IL-3) antibodies inhibited colony formation stimulated by PWM-SCM or ciprofloxacin-PWM-SCM. Fleroxacin and ceftazidime at concentrations of 1 to 100 micrograms/mL and ciprofloxacin at high concentration (greater than 10 micrograms/mL) either did not affect CSF production by spleen cells or had an inhibitory effect. In vivo treatment of sublethally irradiated (650 rad) mice with ciprofloxacin (15 mg/kg per dose three times daily for 5 days) resulted in an increased number of myeloid progenitors in the spleen and bone marrow (BM) of treated mice. In contrast, treatment with ceftazidime did not affect progenitor cell numbers. On days 4 and 8 postirradiation ciprofloxacin-treated mice had a 2.3- and 3.8-fold increase, respectively, in the number of CFU-C in the BM. The number of CFU-C in the spleen did not increase on day 4 postirradiation, but on day 8, the number increased 1.7-fold. On day 4 postirradiation, sublethally irradiated mice treated with ciprofloxacin had a higher WBC count, RBC count, and hemoglobin level as compared with ceftazidime- and saline-treated mice. Twenty-four days postirradiation, 45% of saline-treated mice (20 of 44), and 35% of ceftazidime-treated mice (8 of 23) died, as compared with 13% (5 of 38) of ciprofloxacin-treated mice (P less than .05). These studies indicate that ciprofloxacin may have an immune-enhancing effect on the hematopoietic system in neutropenic mice.

Animals

Immunological aspects of new quinolones.

The effects of new quinolones on the immune system have been mainly studied in vitro. Despite some conflicting results due to variations in study methodologies, certain conclusions can be drawn. Clinically relevant concentrations of most quinolones seem to have no direct effect on isolated immune parameters such as phagocytic cell functions, lymphocyte proliferation, immunoglobulin production, gamma-interferon secretion and bone-marrow progenitor cell proliferation. In contrast, the production of certain cytokines (IL-1, IL-2) and colony stimulating factors by stimulated lymphocytes and splenocytes is enhanced in the presence of clinically achievable concentrations of the drugs. IL-2 production is also enhanced when higher concentrations of quinolones are added to stimulated lymphocytes. However, most other functions such as IL-1 and TNF production, and proliferation of lymphocytes and bone marrow progenitor cells are inhibited in vitro by concentrations of quinolones exceeding 50 micrograms/ml. In vivo studies on immunomodulatory effects of new quinolones are few and are generally in agreement with the in vitro findings. Only very high dosages administered to experimental animals cause suppressive effects, while therapeutic doses are usually not associated with measurable alterations in immune functions. Recent reports on stimulatory effects of therapeutic doses of ciprofloxacin on bone marrow myeloid progenitor cells in irradiated, neutropenic mice, warrant further investigations in experimental animals as well as in neutropenic and bone marrow transplant patients treated with the new quinolones.

4-Quinolones

Oral ofloxacin therapy for invasive external otitis.

The clinical efficacy and safety of orally administered ofloxacin (400 mg twice daily) were evaluated in 24 adult patients (17 men and 7 women; mean age, 65.8 years) with pseudomonal invasive external otitis (IEO). The patients were divided into two groups: group A, (n = 9) suffering from a mild form of IEO, and group B (n = 15), suffering from a more severe form of the disease. Diabetes mellitus was the main underlying disease in these patients. Pseudomonas aeruginosa was the only pathogen in 18 infected ears and part of the polymicrobial flora in an additional 6. Cure was observed in 83.3% of the patients. Two of the cured patients required more than one course of ofloxacin treatment. Development of P aeruginosa resistant to ofloxacin (n = 3) and severe allergic reaction (n = 1) required the discontinuation of ofloxacin therapy. Other side effects such as nausea, arthralgia, and vaginal itching were minimal. Oral administration of ofloxacin seems to be an effective, convenient, relatively safe, and economical therapy of IEO caused by the susceptible organism.

Administration, Oral

All-D-magainin: chirality, antimicrobial activity and proteolytic resistance.

All-D-magainin-2 was synthesized to corroborate experimentally the notion that the biological function of a surface-active peptide stems primarily from its unique amphiphilic alpha-helical structure. Indeed, the peptide exhibited antibacterial potency nearly identical to that of the all-L-enantiomer. Being highly resistant to proteolysis and non-hemolytic all-D-magainin might have considerable therapeutic importance.

Amino Acid Sequence

Use of a ribosomal RNA gene probe for the epidemiological study of methicillin and ciprofloxacin resistant Staphylococcus aureus.

Conventional bacteriophage typing was combined with ribotyping in the analysis of methicillin and ciprofloxacin resistant Staphylococcus aureus strains isolated in increasing frequency since the introduction of the new 4-quinolones as therapeutic agents in the Tel-Aviv Medical Center. Whole-cell DNA was digested with EcoRI and HindIII restriction endonucleases. Agarose gel electrophoresis, Southern blotting, and hybridization by biotinylated probe DNA coding for ribosomal RNA revealed 7 to 14 bands. Analysis of the patterns established a single DNA type in EcoRI as well as in HindIII digests for all strains except one. Control strains from other sources differed in their band patterns. Bacteriophage typing confirmed the results of DNA typing. Thus, the frequent occurrence of staphylococcal isolates resistant to 4-quinolones in the hospital was not due to mutational development of resistance in many strains, but to the spread of a resistant strain.

Anti-Infective Agents

Cross resistance to ciprofloxacin and other antimicrobial agents among clinical isolates of Acinetobacter calcoaceticus biovar anitratus.

Using an agar dilution assay, for 66 of 104 (63.5%) clinical isolates of Acinetobacter calcoaceticus biovar anitratus, the MIC of ciprofloxacin was greater than or equal to 1.0 micrograms/ml. Cross resistance was demonstrable to ciprofloxacin and gentamicin (P less than 0.001), amikacin (P less than 0.01), cefotaxime (P less than 0.001), azlocillin (P less than 0.001), ceftazidime (P less than 0.001), trimethoprim-sulfamethoxazole (P less than 0.001), and minocycline (P less than 0.05). The mean MIC of ciprofloxacin for drug-susceptible isolates was consistently lower than that for resistant isolates; however, these differences were significant only for amikacin (P = 0.036).

Acinetobacter

Widespread quinolone resistance among methicillin-resistant Staphylococcus aureus isolates in a general hospital.

Ofloxacin and ciprofloxacin resistance (MIC, greater than 4 micrograms/ml) was encountered in 45 of 50 clinical isolates of methicillin-resistant Staphylococcus aureus. None of 20 methicillin-susceptible strains was resistant to the quinolones (P less than 10(-6). Quinolone-susceptible and -resistant isolates did not differ with respect to culture source or bacteriophage type. The future usefulness of quinolones for S. aureus infection may be limited.

4-Quinolones

Efficacy of ciprofloxacin against Leptospira interrogans serogroup icterohaemorrhagiae.

Ciprofloxacin activity against Leptospira interrogans serogroup icterohaemorrhagiae was studied in vitro and in an animal model. The MBC of ciprofloxacin was 0.6 microgram/ml. Three of three Syrian hamsters died 8 to 9 days after intraperitoneal challenge with 10(6) leptospires. In contrast, five of six animals given ciprofloxacin 3 or 5 days after challenge survived.

Animals

Enhancement of interleukin-2 production in human lymphocytes by two new quinolone derivatives.

The effect of two quinolone derivatives, ciprofloxacin and ofloxacin, on the production of interleukin-2 (IL-2) was studied in human peripheral blood lymphocytes (PBL) and in a T-cell leukemia cell line (Jurkat) following phytohemagglutinin (PHA) stimulation. Both antimicrobial agents markedly increased IL-2 production in PHA-stimulated PBL cultures. No such effect was observed without PHA stimulation. The effect of the two quinolones on IL-2 production was both time and concentration dependent, reaching a 3-5 fold increase at a drug concentration of 50-100 micrograms/ml, following 24 h incubation. IL-2 synthesized in response to ciprofloxacin or ofloxacin stimulation, exhibited identical chromatographic properties and molecular weight to IL-2 synthesized at standard IL-2 inducing conditions. Only ciprofloxacin enhanced IL-2 production in PHA or in PHA and phorbol myristic acetate (PMA)-stimulated Jurkat cells. The stimulatory effect observed in Jurkat cells at optimal dose concentration (10-50 micrograms/ml), was at most 50% above control levels. In contrast to the effect of ciprofloxacin as a costimulator of IL-2 production in PHA-stimulated PBL, the drug excerted a prominent inhibitory effect on the incorporation of radioactive thymidine and amino acids into these cells. Ciprofloxacin, but not ofloxacin, enhanced interferon (IFN) production in PHA-induced PBL, whereas immunoglobulin M [IgM] production in a SKW6 cell line was enhanced only by ofloxacin.

Biological Assay

Pharmacokinetics of two dosage regimens of ciprofloxacin during a two-week therapeutic trial in patients with cystic fibrosis.

Twenty-nine adult patients with cystic fibrosis received 750 or 1,000 mg of ciprofloxacin orally every 12 hours for two weeks. Pharmacokinetic data were collected on Days 1, 7, and 14. Pharmacokinetic analyses revealed minor differences between the dosage regimens, and results were similar on the first, seventh, and last day of therapy. Means for peak serum concentration (3.1 to 5.0 micrograms/ml), elimination half-life (4.8 to 5.3 hours), area under the time-concentration curve, and serum clearance (36.8 to 44.5 liter/hour) were similar to previously reported results for patients without cystic fibrosis. Sputum concentrations approximated serum values.

Adult

Randomized study of two dosage regimens of ciprofloxacin for treating chronic bronchopulmonary infection in patients with cystic fibrosis.

Twenty-nine adult patients with cystic fibrosis who had chronic bronchopulmonary infection were randomly assigned to receive 750 or 1,000 mg of oral ciprofloxacin every 12 hours for two weeks. Assessments for efficacy and safety were made on treatment Days 7 and 14 and one week following completion of therapy, and pharmacokinetic data were collected on Days 1, 7, and 14. Fifteen of 28 evaluable patients showed clinical improvement, and none had clinical deterioration. The higher dosage of ciprofloxacin did not enhance the clinical response. Statistically significant, stepwise changes in clinical scores, pulmonary function, and sputum concentrations of Pseudomonas aeruginosa and Staphylococcus aureus were noted, but regression toward initial values occurred by one week after treatment. Although all P. aeruginosa isolates were initially inhibited by 2 mg/liter of ciprofloxacin or less, 45 and 35 percent of isolates were resistant after 14 days of therapy and one week later, respectively. Outpatient oral ciprofloxacin therapy was commonly associated with clinical improvement in adult patients with cystic fibrosis who have chronic bronchopulmonary infection, regardless of the emergence of resistant P. aeruginosa, and adverse reactions were infrequent. Further studies must delineate the long-term consequences of the frequent emergence of bacterial resistance.

Adolescent

Synergistic action of amphotericin B and rifampin against Rhizopus species.

A 16-year-old diabetic patient developed Rhizopus pneumonia and was initially treated with amphotericin B for 7 days. Because of clinical deterioration of the patient, rifampin was added empirically. The patient improved clinically, and lung tissue removed surgically 8 weeks later showed no fungal elements by histopathological studies or by culture. An in vitro study of amphotericin B alone and in combination with rifampin against the isolate from the patient and 11 additional isolates of Rhizopus spp. was designed. The activity of amphotericin B in the presence of rifampin (10 or 5 micrograms/ml) increased fourfold against 9 of 10 clinical and 1 of 2 environmental isolates. Amphotericin B activity in the presence of 2 micrograms of rifampin per ml increased fourfold against 6 of 10 clinical isolates and increased twofold against an additional 3 clinical isolates. Amphotericin B in the presence of 1 microgram of rifampin per ml inhibited 9 of 10 isolates at a concentration of one-half the MIC of amphotericin B alone. These findings were confirmed by dose-response curves calculated from fungal dry weight determinations of Rhizopus spp. incubated in serial dilutions of amphotericin B combined with rifampin. These observations demonstrate in vitro, and possibly in vivo, synergy between amphotericin B and rifampin against Rhizopus spp.

Adolescent

Age distribution of anginose mononucleosis.

The age distribution of anginose infectious mononucleosis in children was analysed retrospectively for the years 1966-85. During that period the disease became significantly more common in children of a young age and less common in older children. This shift could not be attributed either to socioeconomic conditions or to the diagnostic methods used.

Adolescent