Structure-activity relationships in antiinflammatory and analgesic compounds chemically related to alpha-isopropyl-alpha-(2-dimethylaminoethyl)-1-naphthylacetamide.
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Analgesics↗
Biomedical subjects
T Bruzzese
Publications and source records attributed to T Bruzzese.
In vivo and in vitro antifungal activity of the polyene derivative SPA-S-753 against encapsulated form of Cryptococcus neoformans.
The in vitro and in vivo activity of SPA-S-753 (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diaspartate), a new water soluble polyene, was compared with amphotericin B against Cryptococcus neoformans in encapsulated (K) and nonencapsulated (N) morphological forms. In vitro tests against 17 isolates of C. neoformans (in K or N form) showed that SPA-S-753 activity is about ten times higher than that of amphotericin B. In direct contact tests the SPA-S-753 cytocidal action was significantly higher than that of amphotericin B; the K cells are, however, less sensitive to the cytocidal action exerted by the two polyenes even when using concentrations 4-fold higher than those used against the N cells and they present a smaller potassium ion release. The cytocidal activity of the two polyenes is favoured by a low electrolyte concentration and an acid pH. SPA-S-753 microbicidal activity by contact in vivo, in mice infected with C. neoformans N cells by i.p. route, is more powerful than that of amphotericin B. In protection tests in mice infected with 10 LD50 of C. neoformans K cells, SPA-S-753 action is again more powerful, but not to a significant degree, than that of amphotericin B. In conclusion, both substances showed a reduced in vitro and in vivo activity against C. neoformans in the K morphological form. Nevertheless our results demonstrate that SPA-S-753 exerts an antifungal overall activity that is more effective than that of amphotericin B under similar experimental conditions.
Amphotericin B↗
Phase I pharmacokinetic study of a new 3-azinomethyl-rifamycin (rifametane) as compared to rifampicin.
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 microg/ml for rifametane and 4.04 microg/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 microg.h/ml for rifametane and 19.9 microg.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.
Administration, Oral↗
Overview of SPA-S-843 in vitro activity against filamentous fungi.
In this study, we investigated the in vitro antifungal activity of a new water-soluble partricin A derivative, N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diascorbate, coded SPA-843, currently developed by Società Prodotti Antibiotici. The activity of SPA-S-843 was compared to that of amphotericin B against 13 strains of Aspergillus spp., 4 strains of Mucor sp., 4 strains of Rhizopus oryzae, 2 strains Paecilomyces variotii, 5 strains of Penicillium spp., 1 strain of Sporothrix schenkii, 7 strains of Trichophyton spp. and 2 strains of Microsporum spp.; the minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) were measured for all the organisms. The in vitro susceptibility testing method employed was an adaptation of the macrodilution reference method for yeasts as described in the National Committee for Clinical Laboratory Standards document M27-A. The in vitro inhibitory activities of SPA-S-843 and amphotericin B against the fungi were evaluated in RPMI-1640 supplemented with L-glutamine and buffered with morpholinepropanesulfonic acid, while the in vitro fungicidal activities were determined by subculturing 0.1 ml from all tubes with no visible growth onto drug-free Sabouraud dextrose agar plates. Comparison with amphotericin B showed that the in vitro inhibitory activity of SPA-S-843 against Aspergillus spp. was better than that of amphotericin B and similar against R. oryzae, P. variotii, Penicillium spp. and S. schenkii. Amphotericin B presented geometric means (GM) of the MICs lower than those of SPA-S-843 against Mucor sp., Microsporum spp. and Trichophyton spp. SPA-S-843 was most fungicidal against Mucor sp. and P. variotii; SPA-S-843 and amphotericin B showed the same fungicidal activity against Aspergillus spp. (GM of the MFCs 12.53 microg/ml), Penicillium spp. (about 12 microg/ml) and S. schenkii (MFC 19.2 microg/ml). Amphotericin B presented GM of the MFC values lower than those of SPA-S-843 against R. oryzae, Microsporum spp. and Trichophyton spp.
Amphotericin B↗
Pharmacokinetics of a new derivative of partricin A (SPA-S-753) in rodents.
Pharmacokinetics of a new semisynthetic polyene antibiotic (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide) in the form of its diaspartate salt (code SPA-S-753) was studied in rats and mice following intravenous injection and in rats following oral administration at different dose levels. In rats the urinary and biliary recovery after intravenous administration was also determined. Rats and mice received a single intravenous injection of 1.25 and 2.5 mg/kg of SPA-S-753 (about 1-2 mg/kg of free base) or 1 mg/kg of amphotericin B as reference drug. Blood samples were obtained at 5 min to 96 h after injection. The half-lives at the elimination phase in serum were 21.3, 26.5, 10.8 h in rats and 11.7, 13.7, 19.8 h in mice, respectively, for 1.25 and 2.5 mg/kg of SPA-S-753 and 1 mg/kg of amphotericin B. The values of AUC(0-infinity) for SPA-S-753 were about 5 times higher in rats and twice higher in mice than those for amphotericin B. Rats received also a single oral dose of 200 or 500 mg/kg of SPA-S-753. Serum samples were obtained at 0.5-96 h after dosing. The compound is poorly absorbed by the oral route. The mean cumulative urinary recovery of SPA-S-753 at 48 h after intravenous injection of 1.25 mg/kg in rats accounts only for 0.5% of the dose, while the cumulative recovery from the bile at 10 h after 2.5 mg/kg i.v. administration in rats accounts for 5.5% of the dose.
Administration, Oral↗
Pharmacokinetics in rats of n-dimethylaminoacetyl-partricin a 2-dimethylaminoethylamide diascorbate (spk-843).
Single- and multiple-administration trials in rats were performed in this study to assess the serum and tissue concentrations of SPK-843 (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diascorbate), a new polyene antibiotic with a heptaene structure. A dose of 1.25 mg/kg (roughly 1 mg/kg of free base) by intravenous route was used both for the single- and multiple-administration trials. The single-administration trial was carried out in comparison with amphotericin B (AmB) at intravenous doses of 1 mg/kg. Plasma samples were drawn at intervals from 15 min to 96 h after injection. The elimination half-lives were 22.15 and 18.15 h, and the area under the curve to infinity (AUC(0-infinity)) values were 35.52 and 10.33 microg.h.ml(-1), respectively, for SPK-843 and AmB. Both drugs showed an extensive tissue distribution, with higher uptake by the kidneys, followed by the liver, spleen and lungs for SPK-843, and higher uptake by the spleen, followed by the lungs, liver and kidneys for AmB. The multiple-administration trial (1.25 mg/kg/day for 7 days) led to sustained serum and tissue concentrations. On the seventh day, the rats were bled at intervals from 5 min to 96 h after dosing. The serum elimination half-life and AUC(0-infinity) values were roughly twice those of the single-dose study (41.4 h and 72.1 microg.h.ml(-1), respectively). Also, the half-lifes and AUCs from 0 to infinity of tissues were greater than those in the single-dose trial.
Amphotericin B↗
The antibacterial activity of a new 3-azinomethyl-rifamycin.
The new 3-azinomethyl-rifamycin, SPA-S-565, was shown to exert an effective antibacterial activity in vitro comparable to that of rifampicin. In fact, the antibacterial activity of SPA-S-565 against numerous Gram-positive cocci belonging to Staphylococcus and Streptococcus species as well as against 20 strains of Mycobacterium tuberculosis, was similar to that of rifampicin. In Swiss albino mice intraperitoneally infected with Staphylococcus aureus Oxford strain or Streptococcus pyogenes, the protective activity of SPA-S-565 and rifampicin was quite remarkable, and no significant difference was noted between the two antibiotics. In M. tuberculosis-infected mice treated with the antibacterial agents every seven days, the protection exerted by SPA-S-565 was significantly greater than that exerted by rifampicin.
Animals↗