The use of lipid emulsions for the i.v. administration of a new water soluble polyene antibiotic, SPK-843.

Venous tolerance of a new water soluble polyene antibiotic, SPK-843, in 5% glucose solution for infusion is low in laboratory animals. The use of Intralipid 10% emulsion was therefore proposed, in which the antibiotic remained chemically stable for at least 2 h in a mildly acid or nearly neutral environment and at concentrations of 0.1-0.5 mg/mL, producing no alterations in the emulsion structure. Tolerance was assessed through repeated infusions in the ear marginal vein of rabbits and was found much more satisfactory than the tolerance observed when the vehicle used was 5% glucose solution. The study of the effect of some variables (concentration, volume infused, dose per kg) on venous toxicity offered the possibility to plan optimal administration conditions of presumed therapeutic doses.

Pharmacokinetics and tissue distribution of rifametane, a new 3-azinomethyl-rifamycin derivative, in several animal species.

Single and repeated dose experiments in mice, rats, dogs and monkeys are reported in this study to assess the pharmacokinetics and tissue distribution of rifametane, a new semi-synthetic rifamycin with the chemical formula 3-[(1-diethylaminoethylidene)azinomethyl]rifamycin SV (CAS 94168-98-6, SPA-S-565). All the kinetic tests were carried out in comparison with known rifamycin derivatives, as rifampicin (CAS 13292-46-1) or rifamycin SV (CAS 6998-60-3). Mice received single i.v. and oral administration of 10 mg/kg of rifametane or of rifampicin and serum samples were obtained up to 96 h after dosing. The two antibiotics showed similar peak of serum concentrations, but rifametane showed a longer half-life and higher AUC values. In an additional experiment, the tissue/serum ratio after the 10 mg/kg oral dose was lower than unity for lungs and kidneys, while the liver/serum ratio exceeded the unity at all sampling times. After 4 weeks of once weekly administration measurable serum and tissue concentrations were observed, and after twice weekly administration for the same time period some blood and tissue accumulation was seen. Rats were treated with a single intravenous injection of 20 mg/kg of rifametane or rifampicin and with single oral or i.m. administration of 60 mg/kg of rifametane or reference standards (rifampicin and rifamycin SV resp.), in two separate trials. The serum half-life of the test antibiotic after i.v. dose was 6 times longer than that of rifampicin and the serum concentrations of rifametane after oral and i.m. doses were higher and longer-lasting than those of the reference compounds. Repeated daily administrations of rifametane at three dose levels (3, 10, 30 mg/kg p.o.) for 4 weeks induced very high serum and liver concentrations. Dogs received a single oral dose of 1.25 mg/kg of rifametane or 2.5 mg/kg of rifampicin. The serum half-life of rifametane resulted 3 times longer than that of rifampicin. Remarkable serum and tissue concentrations were observed after 3-4 weeks of daily oral administration of rifametane at 3, 10, 30 mg/kg dose. Monkeys were given single oral or i.m. administration of 30 mg/kg of rifametane or reference standards (oral rifampicin and i.m. rifamycin SV). The serum concentrations after rifametane were higher and more sustained than those of reference compounds and the half-lives of the test antibiotic were about 2.5 (p.o.) to 6 times (i.m.) longer. The urine excretion of rifametane after a single intravenous dose in rats and a single oral dose in dogs was very low, while rifampicin had a little higher urine concentrations.

[Stability at different pH of polyene antibiotics derived from partricin]. / Stabilità a vari pH di un nuovo antibiotico polienico derivato dalla partricina.

The degradation of a new semisynthetic polyene antibiotic partricin A dimethylamino ethylamide diaspartate (SPA-S-717) at 37 degrees C in water at different pH is studied. It is found to be sensitive to acidic pH and much less sensitive near neutrality. Then a linear relation between pH and logarithm of reaction rate constant is detected. This fact therefore can give some directions as regards the drug somministration in view of pharmacological and clinical trials.