Hans Bundgaard's research while affiliated with Dako Denmark A/S and other places

Publications (201)

Article
The intrinsic dissolution rate of acetylsalicylic acid in 0·1 n hydrochloric acid at 35° has been shown by a rotating disc method to be affected by the presence of acetylsalicylic anhydride in the crystals. At concentrations exceeding 0·25% the impurity decreased the dissolution rate of the acetylsalicylic acid. It is suggested that the previously...
Article
A rapid and convenient colorimetric method is described for the quantitative determination of the immunogenic impurities in acetylsalicylic acid, acetylsalicylsalicylic acid and acetylsalicylic anhydride. The method involves initial aminolysis of the compounds by ammonia to give salicylamide and subsequent coupling of this with 4-amino-phenazone in...
Article
Topically applied O-butyryl timolol, O-pivaloyl timolol and levobunolol (0.25μg) antagonized isoproterenol-induced ocular hypotension for 8 hrs whereas timolol (0.25μg) was shorter acting (4 hrs). Timolol (25μg) produced greater antagonism of isoproterenol-induced tachycardia than did O-butyryl and O-pivaloyl timolol (25μg). These results suggest t...
Conference Paper
Based on the requirements regarding target, reproducibility, and specimen surface quality, an automatic system for controlled material removal and target preparation has been developed. The tool is for metallographic failure analysis of electric and microelectronic components, and provides an accuracy of 5 micrometer. This article presents details...
Article
Using phenyl phoshonate and phenyl phosphate as model compounds for drugs containing these moieties a new type of α-acyloxyalkyl ester derivatives of the OH-groups are introduced. The derivatives both mask the negative charge of these compounds and at the same time are able to release the parent phospho group in vivo in quantitative amounts. The co...
Article
A series of O-cyclopropane carboxylic acid ester prodrugs of various beta-blocking agents was synthesized. All prodrugs were hydrolyzed to give their parent compounds in aqueous phosphate buffer of pH 7.4 and in 80% human plasma. The half-lives in buffer solutions varied from 4 hours for the timolol prodrug to about 1 day for the prodrug of alpreno...
Article
Bioreversible derivatization of mebendazole to improve its poor water solubility, which is attributed to its low peroral bioavailability, was performed by N-acylation of the benzimidazole moiety with various chloroformates. The N-alkoxycarbonyl derivatives were readily hydrolyzed to mebendazole in rabbit liver homogenate and in human and rabbit pla...
Article
N-Hydroxymethylation of the N-terminal peptide bond in N-acetyl-L-phenylalanine amides was found to protect the C-terminal amide bond against cleavage by α-chymotrypsin. The N-hydroxymethyl derivatives are readily bioreversible, undergoing spontaneous hydrolysis at physiological pH, and are thus promising prodrugs to overcome the enzymatic barrier...
Article
A series of phenyl carbamate esters derived from N-substituted 2-aminobenzamides was prepared and evaluated as prodrug forms with the aim of protecting phenolic drugs against first-pass metabolism following peroral administration. The stability of the derivatives was studied in aqueous buffer solutions and in various biological media. The carbamate...
Article
Various aliphatic carboxylic acid esters and a carbonate ester of the tyrosine phenolic group in desmopressin were synthesized to assess their suitability as prodrugs with improved bioavailability compared to the parent peptide. The chemical stability of the esters in aqueous solution was similar to that of simple phenol esters. The derivatives wer...
Article
Possible segmental differences in drug permeability as well as esterase and ketone reductase activities in the albino rabbit intestine were investigated. Beta adrenergic antagonists and timolol prodrugs spanning four orders of magnitude in distribution coefficient were used as model drugs. Drug penetration was evaluated in Ussing chambers using iso...
Article
The in vitro penetration of ketobemidone and various ester prodrugs through porcine buccal mucosa in a modified Ussing chamber was investigated in order to support the selection of a prodrug derivative with optimal buccal absorption. The nine esters studied included carboxylic acid and carbonate esters formed at the phenolic hydroxy group of ketobe...
Article
As part of studies aiming at developing a ketobemidone prodrug suitable for buccal or sublingual administration, the potential impact of saliva enzyme-catalyzed hydrolysis of various ester prodrugs was assessed. The hydrolysis of three ketobemidone esters in human whole saliva, obtained under conditions ensuring maximal esterase activity, was studi...
Article
Saliva enzyme-catalysed hydrolysis of ester prodrugs containing sensitive ester groups may be a limiting factor to the buccal absorption of such compounds. Using the isopropyl carbonate ester of ketobemidone as a model substance of a hydrolysis-sensitive prodrug the esterase activity of human saliva has been characterized as a function of various f...
Article
The buccal absorption of ketobemidone, a strong narcotic analgesic, and various carboxylate and carbonate ester prodrugs was studied in rats. The compounds were administered in the form of aqueous solutions of pH 7.4. The absolute bioavailability of ketobemidone following buccal dosing was 26% whereas the bioavailability of ketobemidone following b...
Article
The feasibility of achieving transdermal delivery of the opioid analgesic kelobemidone was assessed in human skin penetration studies in vitro using both ketobemidone itself and three carbonate ester prodrugs formed at the phenolic hydroxyl group. Whereas ketobemidone itself only showed a limited ability to permeate the skin from either polar or ap...
Article
Various derivatives of the C-terminal amide group in N-protected amino acid and peptide amides were synthesized to assess their suitability as prodrug forms with the aim of protecting the amide or peptide bond against cleavage by alpha-chymotrypsin. Whereas N-acetylation, N-hydroxymethylation, and N-phthalidylation did not afford any protection but...
Article
A major obstacle to the application of peptides as clinically useful drugs is their poor biomembrane penetration, rapid enzymatic degradation and short biological half-lives. A possible approach to solve these delivery problems of peptide drugs is derivatization of the peptides to produce prodrugs or transport forms which are more lipophilic than t...
Article
The hydrolysis kinetics of various alkyl, glycolamide, aminoethyl, and 2-(1-imidazolyl)ethyl esters of ibuprofen and flurbiprofen in 80% human plasma were investigated using a direct high-performance liquid chromatographic assay for the enantiomers of these acids. In each case, the R-isomer ester was found to undergo faster plasma-catalyzed hydroly...
Article
Various aliphatic N-acyl derivatives and an N-phthalidyl derivative of the model compound (Z-Gly-ProNH2) were synthesized to assess their suitability as prodrug forms for the C-terminal prolineamide residue occurring in several peptides (e.g. TRH) with the aim of protecting the peptide against prolyl endopeptidase in the gut prior to absorption. Wh...
Article
The kinetics of degradation of cyclosporin A was studied in aqueous solution at 37 and 60°C over the pH range 0.1–4.0. The predominant degradation reaction at pH < 2 was an isomerization or N,O-acyl rearrangement with formation of isocyclosporin A. A specific acid-catalyzed reaction dominated at pH < 0.5 whereas a spontaneous or water-catalyzed rea...
Article
The kinetics of degradation of isocyclosporin A (isoCyA) was studied in aqueous solution at pH 1–10 and in human plasma. At pH > 5 isoCyA was found to undergo a quantitative conversion to cyclosporin A (CyA) via a mechanism involving intramolecular aminolysis of the ester bond by the N-methyl amino group in the peptide. The pH-rate profile obtained...
Article
The cis/trans isomerization and proton exchange reactions of 3,11b-dimethylbenzodiazepinooxazole (1) in methanol-d4 were investigated kinetically by 1H-NMR spectroscopy. The 3-methyl protons of 1 were followed during the process of isomerization and the pseudo first-order rate constant was determined to be 1.41 × 102 min−1 () at 23°C, irrespective...
Article
Various phenyl carbamate esters derived from amino acids, a dipeptide and amino acid esters and amides were prepared and assessed as potential prodrugs with the aim of protecting phenolic drugs against first-pass metabolism following peroral administration. The stability of the derivatives was studied in aqueous buffer solutions and in various biol...
Article
The bioavailability of noscapine base administered in lozenges in a dose of 100 mg to twelve healthy volunteers, in a study using an open balanced cross-over design, was compared with that of 100 mg of noscapine hydrochloride given perorally as a mixture. The bioavailability of noscapine after administration in lozenges was significantly higher tha...
Article
Oxazolidine ring-opening and ring-closing (acid-base equilibrium) reactions of 3-methyl-11b-hydrogen (1) and −11b-methyl (2) analogues of mexazolam (3) have been studied kinetically in solutions of various pH values and at 25°C. Compound 2 isomerizes to the cis/trans isomers (referring to substituents at the 3- and 11b-position) in methanol-d4 with...
Article
Various N-substituted 3- or 4-(aminomethyl)benzoate 21-esters of hydrocortisone, prednisolone and methylprednisolone were synthesized and evaluated as water-soluble prodrug forms, with the aim of developing improved preparations for parenteral or ophthalmic administration. All esters were readily hydrolyzed enzymatically by human plasma. The half l...
Article
The N-terminal pyroglutamyl group in several peptides is specifically cleaved by pyroglutamyl aminopeptidase (PAPase I). With the aim of protecting this group against enzymatic cleavage by the prodrug approach, various derivatives of L-pyroglutamyl benzylamide, used as a PAPase I sensitive model pyroglutamyl peptide, were prepared and their stabili...
Article
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 a...
Article
Using specific high-pressure liquid chromatography (HPLC) methods, the pharmacokinetics of NNC 0112 and NNC 0756 were studied in mongrel dogs. Both compounds have a low oral bioavailability of 5.4 ± 3.6% (mean ± SD, n = 4) and 6.0 ± 0.5% (n = 4), respectively, due to a large first-pass metabolism. Both compounds were rapidly cleared from the body w...
Article
The oral bioavailability of 1,3-benzoxazine-2,4-dione was investigated in rbbits and compared with that of salicylamide. The benzoxazinedione was shown to be hydrolyzed to salicylamide both in vitro and in vivo. The oral bioavailability of salicylamide was increased 2.5-fold following administration as 1,3-benzoxazinedione compared to oral dosing o...
Article
A major obstacle to the application of peptides as clinically useful drugs is their poor biomembrane penetration, rapid enzymatic degradation and short biological half-lives. A possible approach to solve these delivery problems of peptide drugs is derivatization of the peptides to produce prodrugs or transport forms which are more lipophilic than t...
Article
Various carboxylic acid esters of the N-hydroxymethyl derivative of N-benzyloxycarbonylglycine benzylamide, used as a peptide-like model, were prepared and their decomposition kinetics studied in aqueous solution and in human plasma solutions. These N-acyloxymethylamide derivatives were found to undergo a facile decomposition by a pH-independent pr...
Article
The transepithelial transport of TRH and its prodrug (N-octyloxycarbonyl) derivative was studied using the human colorectal carcinoma cell line Caco-2. No intact TRH prodrug was transported across the cells. Instead, TRH released from the prodrug was absorbed at rates comparable to those of labelled and unlabelled TRH. No metabolites of TRH could b...
Article
Various N-substituted 3- or 4-(aminomethyl)benzoate esters of acyclovir were synthesized and evaluated as water-soluble prodrug forms with the aim of improving the delivery characteristics of acyclovir, in particular its parenteral administration. The esters showed a high solubility in weakly acidic solutions and, as demonstrated with the 3-(N,N-di...
Article
[d-Ala1]-Peptide T amide is an octapeptide presently undergoing clinical evaluation as a potential agent for the treatment of AIDS. As a part of studies aiming at obtaining an oral delivery form of the peptide, its stability towards α-chymotrypsin was examined. The peptide was found to be rapidly degraded by this pancreatic enzyme, the degradation...
Article
The oral bioavailability of 17β-estradiol is only about 10% in humans due to extensive first-pass metabolism. The feasibility of depressing this metabolism and hence improving the systemic bioavailability by the prodrug approach was examined using a rat model. The prodrugs studied included the 17-acetate, 17-valerate, 17-cypionate, 3-benzoate, 3-ac...
Article
Various derivatives of the tyrosine phenol group in N-protected tyrosine amides and esters, used as models of tyrosyl peptides, were synthesized to assess their suitability as prodrug forms with the aim of protecting the tyrosyl peptide bond against cleavage by α-chymotrypsin. The derivatives studied included aliphatic and aromatic carboxylic acid...
Article
Aminopeptidase-catalyzed hydrolysis of Leu-enkephalin and Met-enkephalin is responsible for the rapid metabolism of these pentapeptides in human plasma and at various mucosal sites. The objective of this study was to circumvent this metabolic inactivation by the prodrug approach. A series of 4-imidazolidinone derivatives were prepared by condensing...
Article
Various carbamic acid esters (CAE) of a new class of dopaminergic drugs, 5-substituted 8-chloro-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1 H-3-benzazepines, were synthesized and evaluated as prodrug forms with the aim of protecting the parent phenols against first-pass metabolism following oral administration. Monosubstituted CAE were found to be hig...
Article
N-Phthalidylation of the imidazole group in TRH (pGlu-His-Pro-NH2) was found to be a promising approach to obtain prodrug forms of this tripeptide, with the aim of protecting it against rapid enzymatic inactivation in the systemic circulation. The N-phthalidyl derivative of TRH was shown to be resistant to cleavage by the TRH-specific pyroglutamyl...
Article
The production of alpha-amidated peptides has recently been shown to occur via a two-step process with peptidyl-alpha-hydroxyglycine being an intermediate. In this study the chemical stability and plasma-catalyzed conversion of various peptidyl-alpha-hydroxyglycine derivatives to their parent amide product have been examined. This conversion was sh...
Article
The main objective of this study was to investigate how enzymatic lability would affect the extent of corneal and conjunctival penetration of a series of alkyl, cycloalkyl, and aryl ester prodrugs of timolol in the pigmented rabbit. Enzymatic lability of the prodrugs was studied in corneal epithelial and conjunctival homogenates, while their cornea...
Article
The hydrolysis kinetics and enzymatic cleavage of various N-acyl and N-alkoxycarbonyl derivatives of benzamide, N- methylbenzamide and salicylamide, used as models for the carboxamide group, were studied to assess their suitability as prodrugs for the amide group occurring in various drug substances and bioactive peptides. The pH-rate profiles for...
Article
The feasibility of providing transdermal delivery of morphine was examined using the prodrug approach. Various alkyl esters formed at the 3- and/or 6-hydroxy group in morphine were prepared and their physico-chemical and skin penetration properties studied as well as their hydrolysis kinetics. The esters showed generally a higher water and lipid so...
Article
Various N-alpha-hydroxyalkyl derivatives of N-acyl amino acids and di- and tripeptides were prepared by hydrolysis or aminolysis of N-acyl 5-oxazolidinones. The stability of these derivatives was studied in aqueous solution as a function of pH. The compounds were all degraded quantitatively to their parent N-acylated amino acid or peptide and aldeh...
Article
The kinetics of hydrolysis of a series of 4-imidazolidinones derived from acetone and various di- and tripeptides was studied in aqueous solution and in the presence of enzymes in order to assess their suitability as prodrug forms for the peptides. Whereas the parent di- and tripeptides were readily hydrolyzed by a purified aminopeptidase as well a...
Article
The chemical stability and enzymatic hydrolysis of the mono-, di- and triglycine esters of benzyl alcohol were studied to assess the potential usefulness of peptide esters as water-soluble prodrugs for agents containing a hydroxyl group. All esters were readily hydrolyzed in 80% human plasma to give benzyl alcohol, the half-lives being 69 min for t...
Article
Various N-substituted 3-aminomethylbenzoate esters of chloramphenicol were synthesized and evaluated as water-soluble prodrugs with the aim of developing preparations more suitable for parenteral administration than the presently used monosuccinate ester. This ester shows a variable and incomplete bioavailability due to slow hydrolysis to the paren...
Article
The kinetics of hydrolysis of acyclovir was studied in 0.01-0.5 M hydrochloric acid solutions (pH 0.5-2.2) at 80 degrees C. The hydrolytic cleavage of the 9-C-N bond in acyclovir to give guanine was found to proceed almost quantitatively (greater than 90%) as evidenced by HPLC analysis. The rate of hydrolysis was subject to apparent specific acid c...
Article
The objective of this study was to determine whether the corneal penetration of 5-fluorouracil (5-FU) could be altered by prodrugs. The prodrugs studied included various 1-alkoxy-carbonyl 5-FU derivatives as well as an 1-acyloxymethyl and an 3-acyl derivative. Corneal penetration of 5-FU and its prodrugs was evaluated over 180 min using the isolate...
Article
Various carboxylic acid and carbonate esters of the opioid analgesic ketobemidone were prepared and assessed as potential prodrugs with the aim of obtaining a ketobemidone formulation suitable for buccal or sublingual absorption. The chemical stability, enzymatic hydrolysis and lipophilicity characteristics of the esters were studied using HPLC ass...
Article
The kinetics and mechanism of hydrolysis of 1,3-benzoxazine-2,4-dione and its N-methyl and N-benzoyl derivatives were studied in aqueous solution to provide basic information on the reactivity of the benzoxazinedione structure and to assess the potential of unsubstituted 1,3-benzoxazine-2,4-dione as a prodrug for salicylamide. The compounds were fo...
Article
Bioreversible derivatization of cimetidine to afford more lipophilic prodrugs was performed by N-acyloxymethylation of its imidazole group as well as by N-acylation with various chloroformates. Both the N-acyloxymethyl and N-alkoxycarbonyl derivatives were readily hydrolyzed to cimetidine in human plasma and in rat liver homogenate. The pH-rate pro...
Article
Benzyl carbonate esters of dextran with varying degrees of substitution have been synthesized. The kinetics of the hydrolytic cleavage of the carbonate ester bond in aqueous solution within the pH range 0.44-10.46 (37 degrees C) has been investigated. The degradation reactions followed pseudo-first-order kinetics and a rate expression encompassing...
Article
Various N-substituted 4-(aminomethyl)benzoate diesters of ganciclovir were synthesized and evaluated as prodrug forms with the aim of improving the delivery characteristics of ganciclovir. The esters were hydrolyzed enzymatically by human plasma to the parent drug, the hydrolysis proceeding through formation of the corresponding monoester. The natu...
Article
Chewing gum and lozenges were evaluated as delivery systems for noscapine with the aim of developing improved antitussive preparations. The formulations studied were prepared with both the water-soluble hydrochloride salt of noscapine and with the poorly soluble embonate salt and noscapine free base. The release characteristics of the preparations...
Article
Various derivatives of the C-terminal amide group in N-protected amino acid and peptide amides were synthesized to assess their suitability as prodrug forms with the aim of protecting the amide or peptide bond against cleavage by -chymotrypsin. Whereas N-acetylation, N-hydroxymethylation, and N-phthalidylation did not afford any protection but, in...
Article
The feasibility of providing transdermal delivery of the tripeptide TRH (pGlu-His-Pro-NH2) was examined using the prodrug approach. The prodrugs studied were the N-isobutyloxycarbonyl and N-octyloxycarbonyl derivatives formed by reacting TRH with the appropriate chloroformates at its imidazole moiety. These derivatives are quantitatively converted...
Article
The feasibility of improving the poor oral bioavailability of the tripeptide TRH (pGlu-His-Pro-NH2) was examined using the prodrug approach. The prodrugs studied were various N-alkoxycarbonyl derivatives formed by reacting TRH with the appropriate chloroformates at its imidazole moiety. In vitro metabolism studies with rabbit and rat intestinal hom...
Article
Bioreversible derivatization of TRH (pGlu-His-Pro-NH2) to protect the tripeptide against rapid enzymatic inactivation in the systemic circulation and to improve the lipophilicity of this highly hydrophilic peptide was performed by N-acylation of the imidazole group of the histidine residue with various chloroformates. Whereas TRH was rapidly hydrol...
Article
Various N-substituted [(3- or 4-aminomethyl)benzoyloxymethyl]allopurinol derivatives were synthesized by esterification of 1-(hydroxymethyl)allopurinol and evaluated as water-soluble prodrugs with the aim of developing preparations suitable for parenteral and/or rectal administration. The derivatives combine a good solubility and high chemical stab...
Article
The kinetics of decarboxylation of the antiviral foscarnet (trisodium phosphonoformate) to form carbon dioxide and phosphorous acid was studied in aqueous solutions at 37°C over the pH range 0.2–3.6, using a direct spectrophotometric method as well as an HPLC procedure. The variation of the rate of degradation with pH could be accounted for in term...
Article
The kinetics and mechanism of degradation of the tripeptide TRH (pGlu-His-Pro-NH2) and its various primary and secondary degradation products (TRH-OH, His-Pro-NH2, and His-Pro) have been determined in human plasma at 37 degrees C. The rates of degradation of both TRH and TRH-OH (pGlu-His-Pro) showed mixed zero-order and first-order kinetics. At low...
Article
The systemic bioavailability of N-acetylcysteine (NAC) following oral administration is very low due to extensive first-pass metabolism by deacetylation, primarily in the gut. In an attempt to depress this metabolism and hence increase the systemic bioavailability various esters of NAC were synthesized and assessed as prodrug forms for the parent d...
Article
Various esters of furosemide were prepared and assessed as potential prodrugs with the aim of enhancing the peroral absorption characteristics of the parent drug. The esters studied included a neutral alkyl ester, alkyl esters containing an amino group, glycolamide esters and an O-acyloxymethyl ester. The esters showed widely different susceptibili...
Article
Although it is well-known that N-substituted phthalamic acid derivatives are readily hydrolyzed in acidic aqueous solution due to intramolecular catalysis by the neighbouring carboxy group, sparse information is available on the degradation behaviour in neutral solutions. A recent publication [5] has claimed that N-(3-bromopropyl)phthalamic acid is...
Article
A crucial point in the biosynthesis of cyclo (His-Pro), an endogenous and biologically active cyclic dipeptide, is the spontaneous cyclization of its precursor L-histidyl-L-prolineamide (His-ProNH2). In this study the kinetics and mechanism of the cyclization process has been investigated. His-ProNH2 was found to be converted quantitatively to cycl...
Article
Various N-substituted aminomethylbenzoate esters of metronidazole were synthesized and evaluated as water-soluble prodrugs with the aim of developing preparations suitable for intravenous injection. The esters showed all a high solubility in weakly acidic solutions and were further characterized by possessing a high stability in such solutions allo...
Article
Formation of water-soluble ester prodrugs has long been recognized as an effective means of increasing the aqueous solubility of drugs containing a hydroxyl group, with the aim of developing improved preparations for parenteral or ophthalmic administration. The most commonly used esters for increasing the aqueous solubility of hydroxyl-containing a...
Article
The kinetics of hydrolysis of various alkyl, dicarboxylic acid, carbonate and aromatic 2'-esters of erythromycin was studied in aqueous solution (pH 4–11.5) and human plasma with the aim of developing enzymatically labile erythromycin prodrug esters. The stability of erythromycin was also determined over the pH range 4–10 at 37° C. Whereas the este...
Article
Nalidixic acid has recently been suggested as a potentially useful agent for the treatment of psoriasis. In an attempt to improve the dermal delivery characteristics of nalidixic acid various esters of the compound were synthesized and assessed as prodrug forms for the parent drag. The esters studied include the methyl ester, a glycolamide ester an...
Article
Various N-hydroxyalkyl and N-acyloxyalkyl derivatives of l-pyroglutamyl benzylamide, used as a model pyroglutamyl peptide, were synthesised by reacting it with glyoxylic acid followed by esterification of the carboxy- or hydroxyl group. Whereas the pyroglutamyl benzylamide was rapidly hydrolyzed by pyroglutamyl aminopeptidase, the glyoxylic acid ad...
Article
A series of glycolamide, glycolate, (acyloxy)methyl, alkyl, and aryl esters of acetylsalicylic acid (aspirin) were synthesized and evaluated as potential prodrug forms of aspirin. N,N-Disubstituted glycolamide esters were found to be rapidly hydrolyzed in human plasma, resulting in the formation of aspirin as well as the corresponding salicylate es...
Article
The kinetics and mechanism of degradation of a series of N-sulfonyl imidate esters derived from various model sulfonamides as well as from carbonic anhydrase inhibitors were examined in aqueous solution and in human plasma solutions. The hydrolysis of the compounds was subject to specific acid and base catalysis as well as enzymatic catalysis by pl...
Article
Although the prodrug approach has been generally appreciated as a most useful means to improve the delivery of various drugs, the usual prodrug strategy of preparing a bioreversible derivative or transport form may sometimes fail. In many cases it may be difficult to obtain a prodrug with ideal properties in all respects such as a combination of ad...
Article
The kinetics of hydrolysis of indomethacin and a glycolamide ester of the drug was studied to assess the possibility of designing a water-soluble and solution-stable prodrug of indomethacin suitable for parenteral or ocular administration. The pH-rate profiles for these compounds were obtained at 60 degrees C and were accounted for by specific acid...
Article
Two N-sulfonyl pseudourea derivatives, ethyl N-(p-tolylsulfonyl)-1-pyrrolidinecarboximidate and 3-butyl-2-ethyl-1-p-tolylsulfonylpseudourea, were prepared and evaluated as potential prodrug forms for the primary sulfonamide group in the model p-toluenesulfonamide. The stability characteristics of the compounds were examined in aqueous solution at v...
Article
Various N-acyl derivatives and N-Mannich bases of the model compound L-pyroglutamyl benzylamide were synthesized to assess their suitability as prodrug forms for the N-terminal pyroglutamyl residue occurring in several peptides, with the aim of improving peptide delivery characteristics. Whereas pyroglutamyl benzylamide was rapidly hydrolyzed by py...
Article
The kinetics of hydrolysis of cimetidine was studied in 0.01-1 M hydrochloric acid solutions (pH 0.15-2.15) at 37 degrees C. The hydrolytic cleavage of the cyanoguanidino group in cimetidine to give a guanylurea derivative was found to proceed quantitatively, as evidenced by HPLC analysis. The rate of hydrolysis was subject to specific acid catalys...
Article
Various N-acyl derivatives (acetyl, benzoyl, N, N-diethylaminoacetyl and morpholinoacetyl) of the model sulfonamide N-methyl-p-toluenesulfonamide were synthesized and evaluated as potential prodrug forms for the sulfonamide group occurring in e.g. carbonic] anhydrase inhibitors. The kinetics of hydrolysis of the derivatives were determined at 37°C...
Article
Topically applied O-butyryl timolol, O-pivaloyl timolol and levobunolol (0.25 micrograms) antagonized isoproterenol-induced ocular hypotension for 8 hrs whereas timolol (0.25 micrograms) was shorter acting (4 hrs). Timolol (25 micrograms) produced greater antagonism of isoproterenol-induced tachycardia than did O-butyryl and O-pivaloyl timolol (25...
Article
Some lower aliphatic esters of timolol have previously been developed as prodrugs to potentially diminish the systemic absorption and hence side-effects of topically applied timolol through increased corneal absorption. Although these esters are promising timolol prodrugs for ocular delivery, they suffer from instability in aqueous solution. In thi...
Article
The hydrolysis kinetics of six N-acyl 5-oxazolidinones derived from various N-benzyloxycarbonyl amino acids and aldehydes (formaldehyde, acetaldehyde and benzaldehyde) was studied to assess their suitability as prodrug forms for the α-amido carboxy moiety occurring in peptides. The degradation of the compounds was shown to take place by hydrolytic...