- Synthesis of pH-sensitive amphotericin B-poly(ethylene glycol) conjugates and study of their controlled release in vitro
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New intravenous conjugates of amphotericin B (AMB) with poly(ethylene glycols) (PEG) (M = 5000, 10,000, 20,000) have been synthesized and characterised. The intermediate PEGs possess a 1,4-disubstituted benzene ring with aldehyde group at the end of the chain. The benzene ring is connected with PEG at its 4-position (with respect to the aldehyde group) by various functional groups (ether, amide, ester). Reaction of terminal aldehyde group of the substituted PEGs with AMB gave conjugates containing a pH-sensitive imine linkage, which can be presumed to exhibit antimycotic effect at sites with lowered pH value. All types of the conjugates are relatively stable in phosphate buffer at physiological conditions of pH 7.4 (37 °C), less than 5 mol% AMB being split off from them within 24 h. For a model medium of afflicted tissue was used a phosphate buffer (pH 5.5, 37 °C), in which controlled release of AMB from the conjugates takes place. The imine linkage is split to give free AMB with half-lives of 2-45 min. The rate of acid catalysed hydrolysis depends upon substitution of the benzene ring; however, it does not depend on molecular weights of the PEGs used. The conjugates with ester linkage undergo enzymatic splitting in human blood plasma and/or blood serum at pH 7.4 (37 °C) with half-lives of 2-5 h depending on molecular weights of the PEGs used (M = 5000, 10,000, 20,000). At first, the splitting of ester linkage produces the relatively stable pro-drug, that is, 4-carboxybenzylideniminoamphotericin B, which is decomposed to AMB and 4-formylbenzoic acid in a goal-directed manner only at pH 7 (t1/2 = 2 min, pH 5.5, 37 °C). A goal-directed release of AMB is only achieved by acid catalysed hydrolysis of imine linkage, either from the polymeric conjugate or from the pro-drug released thereof. The LD50 values determined in vivo (mouse) are 20.7 mg/kg and 40.5 mg/kg for the conjugates with ester linkage (M = 10,000 and 5000, respectively), which means that they are ca. 6-11 times less toxic than free AMB.
- Sedlak, Milos,Pravda, Martin,Staud, Frantisek,Kubicova, Lenka,Tycova, Katerina,Ventura, Karel
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- Synthesis and characterisation of a new pH-sensitive amphotericin B-poly(ethylene glycol)-b-poly(l-lysine) conjugate
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This paper reports on the synthesis, characterisation, and efficiency of a new intravenous conjugate of amphotericin B (AMB). Twelve molecules of AMB were attached to block copolymer poly(ethylene glycol)-b-poly(l-lysine) via pH-sensitive imine linkages. In vitro drug release studies demonstrated the conjugate (Mw = 26,700) to be relatively stable in human plasma and in phosphate buffer (pH 7.4, 37 °C). Controlled release of AMB was observed in acidic phosphate buffer (pH 5.5, 37 °C) with the half-life of 2 min. The LD50 value determined in vivo (mouse) is 45 mg/kg.
- Sedlak, Milos,Pravda, Martin,Kubicova, Lenka,Mikulcikova, Petra,Ventura, Karel
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- Anti-CD22 antibodies
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Anti-CD22 antibodies, including isolated nucleic acids that encode at least one such anti-CD22 antibody, vectors, host cells, transgenic animals or plants, and methods of making and using thereof, including therapeutic compositions, methods and devices.
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- POLYENE DIESTER ANTIBIOTICS
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The present invention discloses a new polyene diester and its preparation. This polyene diester has a structure of Formula 1, which is used as prodrugs by introducing diester group to polyene antibiotics, and these prodrugs exhibit antifungal or antiviral activities through releasing parent polyenes by esterase in vivo. The new derivatives have good antimicrobial activity and better safety. These new derivatives are useful for the antifungal and antiviral treatment. PA-COOR Formula 1
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(2010/08/22)
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- Polyene macrolide derivatives, use for vectoring molecules
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A composition having a negatively charged molecule and a cationic polyene macrolide compound having two to four positive charges that reacts with the negatively charged molecule is described. This compound can be used to vector molecules and especially nucleic acids into cells.
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- Method for apparatus for a defined serumfree medical solution useful for corneal preservation
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A defined serumfree medical solution for applications in Ophthalmology, that contains one or more cell nutrient supplements which maintains and enhances the preservation of eye tissues, including human corneal tissues at low temperatures (2° C. to 15° C.). This solution is composed of a defined aqueous nutrient and electrolyte solution, supplemented with a glycosaminoglycan(s), a deturgescent agent(s), an energy source(s), a buffer system(s), an antioxidant(s), membrane stabilizing components, antibiotic(s), ATP precursors and nutrient cell supplements.
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- Prodrug derivatives of carboxylic acid drugs
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Novel ester derivatives of carboxylic acid medicaments of formula (I), wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integrer from 1 to 3, and R1 and R2 are the same or different and are selected from a group consisting of an alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may be unsubstituted or substituted, or R1 and R2 together with the N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which heterocyclic group may be substituted. These compounds are highly biolabile prodrug forms of the corresponding carboxylic acid compounds and are highly susceptible to undergoing enzymatic hydrolysis in vivo whereas they are highly stable in aqueous solution. The novel derivatives are less irritating to mucosa than the parent carboxylic acids and may provide an improved bio-availability of the drugs.
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- Process and composition for the purification of amphotericin B
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A unique four-solvent system comprising methanol, dimethylformamide, methylene chloride and water is employed to provide an improved process for the purification and crystallization of amphotericin B.
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