Acta pharmaceutica Nordica最新文献

The ocular permeability of two sieved fractions of prednisolone acetate with a mean particle size of less than 5 microns and 5-10 microns was studied in rabbits. The results show that there was not significant difference between the corneal uptake of the two fractions of prednisolone acetate. Prednisolone acetate was rapidly taken up by the cornea where it is hydrolyzed rapidly to prednisolone. Only prednisolone was detected in the aqueous humor showing that prednisolone acetate is completely hydrolyzed in the cornea. Both fractions produced similar concentrations of prednisolone in the aqueous humor. For prednisolone acetate, the permeability rate rather than the dissolution rate seems to be the rate-limiting step for corneal transport.

Synthesis and structure of some analogs of the omeprazole containing furan and thiophene rings are reported. Their effects on the basal and the histamine-stimulated secretion were evaluated on the isolated rat stomach.

Insulin decomposes by a multitude of chemical reactions [1-3]. It deamidates at two different residues by entirely different mechanisms. In acid, deamidation at AsnA21 is intramolecularly catalyzed by the protonated C-terminal, whereas above pH 6 an intermediate imide formation at residue AsnB3 leads to isoAsp and Asp derivatives. The imide formation requires a large rotation around the alpha-carbon/peptide carbonyl carbon bond at B3, corresponding to a 10 A movement of the B-chain N-terminal. The main determinant for the rate of B3 deamidation, as well as for the ratio between the two products formed, is the local conformational structure, which is highly influenced by various excipients and the physical state of the insulin. An amazing thermolysin-like, autoproteolytic cleavage of the A-chain takes place in rhombohedral insulin crystals, mediated by a concerted catalytic action by several, inter-hexameric functional groups and Zn2+. Intermolecular, covalent cross-linking of insulin molecules occurs via several mechanisms. The most prominent type of mechanism is aminolysis by the N-terminals, leading to isopeptide linkages with the A-chain side-chain amides of residues GlnA15, AsnA18 and AsnA21. The same type of reaction also leads to covalent cross-linking of the N-terminal in protamine with insulin. Disulfide exchange reactions, initiated by lysis of the A7-B7 disulfide bridge, lead mainly to formation of covalent oligo- and polymers. Activation energy (Ea) for the neutral deamidation and the aminolysis reactions was found to be 80 and 119 KJ/mol, respectively.

The poor peroral absorption of benzimidazole anthelmintics limits their usefulness for the treatment of systemic infections such as alveolar or cystic echinococcosis. The low bioavailability has mainly been attributed to the low aqueous solubility of the benzimidazoles. Using thiabendazole as a model compound the prodrug approach was investigated as a mean to obtain derivatives with improved water-solubilities. Bioreversible derivatization of thiabendazole was performed by N-acylation of the benzimidazole moiety with various chloroformates as well as by N-acyloxymethylation. Both the N-alkoxycarbonyl and the N-acyloxymethyl derivatives were readily hydrolyzed to thiabendazole in human plasma and in rat and pig liver homogenates. The pH-rate profiles for the hydrolysis of the derivatives were determined and the lipophilicity of the compounds was assessed by partition experiments. The water-solubility of the N-alkoxycarbonyl derivatives was up to 12 times higher than that of the parent drug. An N-(4-amino-methylbenzoyl)oxymethyl derivative possessed a 300-fold higher water-solubility. The improved aqueous solubility, adequate lipophilicity and chemical stability combined with a facile enzymatic hydrolysis make such derivatives promising prodrugs for benzimidazole anthelmintics with the aim of improving the peroral bioavailability.

During storage of insulin formulated for therapy, minor amounts of various degradation and covalent di- and polymerization products are formed [1-3]. The main chemical transformation products were isolated from aged preparations and characterized chemically and biologically. The most prominent products formed in neutral medium were identified as a mixture of deamidation products hydrolyzed at residue B3, namely isoAsp B3 and Asp B3 derivatives. A hydrolysis product formed only in crystals of insulin zinc suspensions containing a surplus of zinc ions in the supernatant was identified as an A8-A9 cleavage product. The small amounts of covalent insulin dimers (CID) formed in all formulations were shown to be a heterogenous mixture of 5-6 different CIDs with a composition dependent on the pharmaceutical formulation. The chemical characteristics of the CIDs indicate that they are formed through a transamidation reaction mainly between the B-chain N-terminal and one of the four amide side-chains of the A chain. GlnA15, AsnA18 and, in particular, AsnA21 participate in the formation of such isopeptide links between two insulin molecules. The covalent insulin-protamine products (CIPP) formed during storage of NPH preparations presumably originate from a similar reaction between the protamine N-terminal with an amide in insulin. Covalent polymerization products, mainly formed during storage of amorphously suspended insulin at higher temperature, were shown to be due to disulfide interactions. Biological in vivo potencies relative to native insulin were less than 2% for the split-(A8-A9)-product and for the covalent disulfide exchange polymers, 4% for the CIPP, approximately 15% for the CIDs, whereas the B3 derivatives exhibited full potency. Rabbit immunization experiments revealed that none of the insulin transformation products had significantly increased immunogenicity in rabbits.

An ethanol extract of the fruits of Solanum tuberosum was partitioned between water and petroleum ether. The aqueous fraction had contractive effect on the isolated guinea-pig ileum. Chromatography of this fraction on Sephadex LH-20 and silica gel was monitored by the guinea-pig ileum test and resulted in isolation of serotonin. HPLC analysis of the content of serotonin in fruits, leaves and tubers of the plant, showed that the fruits and leaves contained 7.5 micrograms and 2 micrograms, respectively, of serotonin/g fresh weight. In agreement with previous observations, no serotonin was detected in the tubers.

4-Phenyl-5,5-dicarbethoxy-2-pyrrolidenone [XIV] treatment in Sprague Dawley rats caused significant reduction of serum cholesterol and triglyceride levels with reduction of VLDL and LDL cholesterol levels. The compound significantly reduced regulatory enzyme activities, e.g. ATP dependent citrate lyase, HMG CoA reductase, acyl CoA cholesterol acyl transferase, cholesterol-7-alpha-hydroxylase, sn-glycerol-3-phosphate acyl transferase and phosphatidylate phosphohydrolase. In tissue cultured cells, the compound suppressed LDL receptor activity and degradation, and elevated HDL receptor activity and HDL degradation. Rat bile cholesterol and phospholipids were elevated; however, overall bile acids were reduced. In situ loop studies suggest that the agent interfered with interhepatic reabsorption of cholesterol and cholic acids. At the therapeutic dose of compound XIV, no deleterious effects were demonstrated in mice.

The structure and absolute configuration of the title compound have been determined by single crystal X-ray diffraction analysis. The space group symmetry is R21; the monoclinic unit cell contains two molecules and has the dimensions a = 12.4291(8), b = 7.4511(5), c = 12.7854(7) angstroms and beta = 102.295(7) degrees. The planar conformation of the benzamide moiety is stabilized by an intramolecular (N)H...O bond. Hydrogen bonds connect the chloride anion to the protonated pyrrolidine N atom, and also the crystal water to the carbonyl oxygen of the amide group. The molecule has a folded conformation in which the N-fluorobenzyl substituent of the pyrrolidine ring and the H-bonded pseudo ring of the benzamide moiety are arranged in a sandwich-like manner. In the crystal, intermolecular hydrogen bonds link the drug molecules via the chloride anion and the hydrate molecule into endless helical chains around the twofold axis. The absolute configuration was determined by comparison of the wRtot values, 0.037 and 0.040, calculated using all measured 2027 unique, non-zero reflections and assuming R and S configuration for the chiral center, respectively. Refinement of the structural model with an R configuration resulted in the final indices of R = 0.031 and wR = 0.033 for 1512 reflections with I/delta(I) greater than 3.