- Epimerization kinetics of moxalactam, its derivatives, and carbenicillin in aqueous solution
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The mechanism of the epimerization of moxalactam was studied by measuring the rate of epimerization after deuteration of the C-7 side-chain chiral carbon, introduction of different substituents on the side chain, and variation of the ring system. Deuteration slowed the epimerization rate considerably. The rate was also influenced by the choice of the ring system and the substituent on the C-7 side-chain chiral carbon. When the penicillin ring system with the 2-carboxy-2-phenylacetamide was studied, the epimerization rate decreased indicating that the same ring system needed to be used throughout the epimerization studies. Thus, experiments were conducted with different substituents replacing the phenolic group at the C-7 side-chain chiral carbon of moxalactam. The epimerization rate decreased in the substituent order thienyl, phenyl, 4-hydroxyphenyl, the ionized form of 4-hydroxyphenyl, and ethyl. These results showed that dehydrogenation of the chiral carbon seems to be the rate-determining step and that the stronger the electron-donating effect of the substituent, the slower the epimerization rate becomes.
- Hashimoto,Tanaka
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- MODIFIED TNFalpha MOLECULES, DNA ENCODING SUCH MODIFIED TNFalpha MOLECULES AND VACCINES COMPRISING SUCH MODIFIED TNFalpha MOLECULES AND DNA
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New modified human tumour necrosis factoralpha , TNFalpha , (I) , able to generate, in humans, neutralising antibodies (Ab) to wild-type human TNFalpha (Ia): (a) has >= 1 fragment of TNF substituted by a peptide containing an immunodominant T-cell epitope, or (b) is a truncated form of (a) containing an immunodominant epitope and one or both flanking regions of TNF, including >= 1 TNFalpha B-cell epitope. The substitution causes a significant change in the amino acid (aa) sequence of any one of the strands in the front beta -sheet (fbS), any of the connecting loops and/or any of the B', I or D strands in the back beta -sheet (bbS). Also new are: (1) dimers, oligomers and multimers of (I); (2) isolated DNA (II) that encodes (I); (3) (expression) vectors containing (II); (4) hosts transformed with the expression vector, and (5) fusion proteins (FP) of (I) with an immunological adjuvant.
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- Method of using deuterated calcium channel blockers
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Therapeutic methods and compositions using deuterated enriched 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester and other deuterated dihydropyridine compounds are described. The deuterated compounds exhibit enhanced efficacy in blocking calcium channels over non-deuterated dihydropyridines.
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- Enhancement of the efficacy of nifedipine by deuteration
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A method of enhancing the efficiency and increasing the duration of action of drugs (e.g. dihydropyridines and anti-bacterials) and particularly of nifedipine and penicillins wherein one or more hydrogen atoms are deuterated and wherein the deuterated drug has unexpectedly improved properties when used in much lower concentrations than unmodified drug. A method for determining the identity and bioequivalency of a new drug is also disclosed wherein the molecular and isotope structure of a new drug is determined by isotope ratio mass spectrometry and compared with the molecular and isotope structure of a known human drug.
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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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- Intermediates for preparing α-carboxy-α-(3-thienyl)penicillin and cephalosporin derivatives
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A new process is disclosed for the preparation of alpha-carboxy-alpha-phenyl(or 3-thienyl)penicillin and cephalosporin derivatives. The process comprises reacting a 1.3-dioxane-4.6-dione derivative with the desired penicillanic or cephalosporanic acid derivative.
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