Biomedical subjects
Publications and source records attributed to M Fortuna.
In this paper the synthesis and antithrombotic activity of a series of novel thrombin inhibitors with azaphenylalanine scaffold are described. By systematic structural modifications for this series we have identified optimal groups for achieving nanomolar potency, that led to potent inhibitors of thrombin with Ki values up to 11 nM.
To evaluate the Toxocara spp. eggs environmental contamination of the soil of the urban or suburban area Ancona (Italy), 22 public playgrounds were selected and several cores of soil were taken from any selected areas. To study the Toxocara seroprevalence in the inhabitants of Ancona, blood samples were collected from selected groups of individuals. One hundred and sixty-three blood samples were tested using an enzyme linked immunosorbent assay (ELISA) technique (Lofarma Lab, Milan, Italy) for the detection of IgG-specific antibodies to T. canis excretory-secretory antigens. Toxocara spp. eggs were found in the soil samples from 14 (63.6%) playgrounds. Toxocara seroprevalence was detected in blood specimens from six (8.1%) out of 74 symptomatic individuals and from one (1.1%) out of 89 asymptomatic controls. Among symptomatic individuals, the association between Toxocara seroprevalence and eosinophilia resulted statistically significant (p = 0.029). The high environmental contamination frequency found make necessary to prompt preventive public health measures, such as control of stray animals, treatment of infected pets and hygiene education of the population.
The in vitro susceptibilities of 90 clinical isolates of gram-positive and gram-negative aerobic bacteria to six cationic peptides, buforin II, cecropin P1, indolicidin, magainin II, nisin, and ranalexin, were evaluated by two broth microdilution methods. The first method was performed according to the procedures outlined by the National Committee for Clinical Laboratory Standards for bacteria that grow aerobically, while the second was performed according to the procedures recently proposed by the R. E. W. Hancock laboratory for testing antimicrobial peptides. Overall, the first method produced MICs two- and fourfold higher than the second method.
The in vitro activities of buforin II, cecropin P1, and magainin II, alone and in combination with six clinically used antimicrobial agents, against 12 clinical isolates of Stenotrophomonas maltophilia were investigated. Antimicrobial activities were measured by MIC and time-kill studies. The isolates were susceptible to the peptides at concentrations in the range of 0.50 to 16 microg/ml. Synergy was observed when the peptides were combined with polymyxin E, meropenem, ceftazidime, piperacillin, and clarithromycin.
The interaction of amphotericin B (AmB) and azole antifungal agents in the treatment of fungal infections is still a controversial issue. A checkerboard titration broth microdilution-based method that adhered to the recommendations of the National Committee for Clinical Laboratory Standards was applied to study the in vitro interactions of AmB with fluconazole (FLC), itraconazole (ITC), and the new investigational triazole SCH 56592 (SCH) against 15 clinical isolates of Cryptococcus neoformans. Synergy, defined as a fractional inhibitory concentration (FIC) index of < or =0.50, was observed for 7% of the isolates in studies of the interactions of both FLC-AmB and ITC-AmB and for 33% of the isolates in studies of the SCH-AmB interactions; additivism (FICs, >0.50 to 1.0) was observed for 67, 73, and 53% of the isolates in studies of the FLC-AmB, ITC-AmB, and SCH-AmB interactions, respectively; indifference (FICs, >1.0 to < or =2.0) was observed for 26, 20, and 14% of the isolates in studies of the FLC-AmB, ITC-AmB, and SCH-AmB interactions, respectively. Antagonism (FIC >2.0) was not observed. When synergy was not achieved, there was still a decrease, although not as dramatic, in the MIC of one or both drugs when they were used in combination. To investigate the effects of FLC-AmB combination therapy in vivo, we established an experimental model of systemic cryptococcosis in BALB/c mice by intravenous injection of cells of C. neoformans 2337, a clinical isolate belonging to serotype D against which the combination of FLC and AmB yielded an additive interaction in vitro. Both survival and tissue burden studies showed that combination therapy was more effective than FLC alone and that combination therapy was at least as effective as AmB given as a single drug. On the other hand, when cells of C. neoformans 2337 were grown in FLC-containing medium, a pronounced increase in resistance to subsequent exposures to AmB was observed. In particular, killing experiments conducted with nonreplicating cells showed that preexposure to FLC abolished the fungicidal activity of the polyene. However, this apparent antagonism was not observed in vivo. Rather, when the two drugs were used sequentially for the treatment of systemic murine cryptococcosis, a reciprocal potentiation was often observed. Our study shows that (i) the combination of triazoles and AmB is significantly more active than either drug alone against C. neoformans in vitro and (ii) the concomitant or sequential use of FLC and AmB for the treatment of systemic murine cryptococcosis results in a positive interaction.
The prevalence of Blastocystis hominis in stool specimens of individuals with gastrointestinal symptoms was evaluated to study a possible link between the protozoan and the irritable bowel syndrome. According to the Rome diagnostic criteria, 388 patients were evaluated. Altogether, 81 patients were classified as affected by irritable bowel syndrome. Blastocystis hominis was recovered from the stools of 38 subjects, 15 of whom belonged to the group with irritable bowel syndrome (P = 0.006). In addition, patients with irritable bowel syndrome were significantly more likely to have five or more Blastocystis hominis organisms per field (P = 0.031). In conclusion, there was a set of patients with irritable bowel syndrome in whom the presence of Blastocystis hominis may not be incidental.
The in vitro activity of ranalexin alone and in combination with other cationic peptides, macrolides, rifampin, and rifabutin was investigated against a clinical isolate of Cryptosporidium parvum. Susceptibility tests were performed by inoculation of the isolate onto cell monolayers and determining the parasite count after 48 h of incubation at 37 degrees C. Antibiotic-free cultures were used as controls in the study. Ranalexin showed low anticryptosporidial activity: it suppressed the growth of parasites by > or = 40% at 50 microM. Ranalexin showed enhanced activity when it was combined with noninhibitory concentrations of other compounds: a 74.4-94.1% reduction in the number of parasites was observed when ranalexin 50 microM was combined with magainin II 50 microM, indolicidin 50 microM, clarithromycin 8 mg/l, azithromycin 8 mg/l, rifampin 8 mg/l, and rifabutin 8 mg/l. The results suggest that ranalexin may be effective in inhibiting Cryptosporidium parvum growth in vitro upon combination with other peptides and hydrophobic antibiotics.
The in-vitro activity of cecropin P1, indolicidin, magainin II, nisin and ranalexin alone and in combination with nine clinically used antimicrobial agents was investigated against a control strain, Pseudomonas aeruginosa ATCC 27853 and 40 clinical isolates of P. aeruginosa. Antimicrobial activities were measured by MIC, MBC and viable count. In the combination study, the clinically used antibiotics were used at concentrations close to their mean serum level in humans in order to establish the clinical relevance of the results. To select peptide-resistant mutants, P. aeruginosa ATCC 27853 was treated with consecutive cycles of exposure to each peptide at 1 x MIC. The peptides had a varied range of inhibitory values: all isolates were more susceptible to cecropin P1, while ranalexin showed the lowest activity. Nevertheless, synergy was observed when the peptides were combined with polymyxin E and clarithromycin. Consecutive exposures to each peptide at 1 x MIC resulted in the selection of stable resistant mutants. Cationic peptides might be valuable as new antimicrobial agents. Our findings show that they are effective against P. aeruginosa, and that their activity is enhanced when they are combined with clinically used antimicrobial agents, particularly with polymyxin E and clarithromycin.
The in-vitro activity of rifabutin and albendazole alone and in combination with clarithromycin, etoposide, minocycline and pyrimethamine was investigated against four clinical isolates of Pneumocystis carinii. The susceptibility tests were performed by inoculation of the isolates on to cell monolayers and by determining the parasite count after 72 h incubation at 37 degrees C. The culture medium was supplemented with serial dilutions of each agent. Albendazole tested alone was more active than rifabutin. Albendazole suppressed the growth of cysts and trophozoites by >50% at 4 mg/L. Rifabutin, at the same concentration, produced about 40% reduction in the mean cyst and trophozoite counts. Albendazole (4 mg/L) combined with etoposide 4 mg/L showed the highest anti-P. carinii activity, with a decrease of 86.3% and 90.1% in cyst and trophozoite counts, respectively. The greatest synergic interaction was detected when rifabutin (4 mg/L) was combined with clarithromycin (4 mg/L). Our study suggests that clinically used antimicrobial agents may be effective in inhibiting P. carinii growth in vitro and that, above all, some of these agents possess a positive interaction upon combination with other clinically used compounds. These findings may be useful in the establishment of a prophylaxis regimen for multiple opportunistic pathogens.
The in vitro activities of magainin II, nisin, and ranalexin alone and in combination with other antimicrobial agents against six clinical isolates of Rhodococcus equi were investigated by MIC and time-kill studies. All isolates were more susceptible to nisin. A positive interaction was observed when the peptides were combined with ampicillin, ceftriaxone, rifabutin, rifampin, azithromycin, clarithromycin, and vancomycin.
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Shoulder problems are common in overhead sports like baseball, basketball and volleyball. Although gymnastics also includes overhead activities, there are few reports about shoulder problems in this sports activity. During the time period 1992-1995 we treated five young competitive gymnasts for shoulder pain. Arthroscopy revealed that they were all suffering from SLAP lesions or other labral pathology, although they had never dislocated their shoulders. These injuries have not been described earlier in connection with gymnastics. In a survey of 13 gymnasts in an elite club, we found that six (46%) complained about shoulder pain. Since four of these athletes explained that their shoulder pain started acutely during ring exercises in suspension while one suffered a slower onset with pain also during parallel bar exercises, we undertook an electromyographic study of the shoulder musculature of three normal elite gymnasts during exercises on the parallel bars and rings. We found that during the ring exercises in suspension there was a "critical phase" during which the muscle activity around the shoulder was very low, leading to great articular stresses. This might explain the occurrence of labral lesions like the SLAP lesions in this type of athlete. If shoulder pain in elite gymnasts does not respond to rest and physical therapy over 2-3 months, a shoulder arthroscopy should be considered.
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Cryptophycin 1 is a natural product that was initially isolated from blue-green algae which has shown potent broad spectrum antitumor activity in preclinical in vitro and in vivo models. The drug strongly binds to tubulin and disrupts microtubule assembly for more than 24 hours after its removal. We evaluated cell survival, intracellular levels and inhibition of macromolecular synthesis in L1210 cells following exposure to cryptophycin 1 in vitro. Cell survival was strongly inhibited following drug exposure for either 1 or 4 hours. Intracellular drug levels were minimally affected by temperature (4 degrees C versus 37 degrees C) or exposure times up to 1 hour. However, extracellular drug concentration in culture media and increasing cell numbers did affect the concentration of intracellular drug levels in a nearly proportional manner. The synthesis of DNA and RNA was inhibited less than 5%, while protein synthesis inhibition was near 30%. Thus, none of the macromolecules were inhibited enough to explain the inhibition of tumor cell growth.
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