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Biomedical subjects

H Bundgaard

Publications and source records attributed to H Bundgaard.

At least 55 records · Page 3Linked to original sources
PubMed1995

Digoxin affects potassium homeostasis during exercise in patients with heart failure.

OBJECTIVE: The aim was to evaluate whether digitalisation of heart failure patients affects extrarenal potassium handling during and following exercise, and to assess digoxin receptor occupancy in human skeletal muscle in vivo. METHODS: In a paired study of before versus after digitalisation, 10 patients with congestive heart failure underwent identical exercise sessions consisting of three bouts of increasing work rates, 41-93 W, on a cycle ergometer. The final bouts were followed by exercise to exhaustion. The femoral vessels and brachial artery were catheterised. Arterial blood pressure, heart rate, leg blood flow, cardiac output, plasma potassium, haemoglobin, pH, and skeletal muscle receptor occupancy with digoxin in biopsies were determined. RESULTS: Occupancy of skeletal muscle Na/K-ATPase with digoxin was 9% (P < 0.05). Following digitalisation femoral venous plasma potassium increased by 0.2-0.3 mmol.litre-1 (P < 0.05) at work rates of 69 W, 93 W, and at exhaustion, as well as during the first 3 min of recovery. Following digitalisation the femoral venoarterial difference in plasma potassium increased by 50-100% (P < 0.05) during exercise, and decreased by 66-75% (P < 0.05) during early recovery. Total loss of potassium from the leg increased by 138%. The effects of digitalisation on plasma potassium were not the outcome of changes in haemodynamics, because cardiac output and leg blood flow increased by up to 13% and 19% (P < 0.05), nor was it the outcome of changes in haemoconcentration or pH. CONCLUSIONS: Extrarenal potassium handling is altered as a result of digoxin treatment. This is likely to reflect a reduced capacity of skeletal muscle Na/K-ATPase for active potassium uptake because of inhibition by digoxin, adding to the reduction of skeletal muscle Na/K-ATPase concentration induced by heart failure per se. In heart failure patients, improved haemodynamics induced by digoxin may, however, increase the capacity for physical conditioning. Thus the impairment of extrarenal potassium homeostasis by heart failure and digoxin treatment may be counterbalanced by training.

Cardiac Output↗
PubMed1994

[Aortic stenosis. Occurrence, pathogenesis, diagnostic strategy and therapeutic indications].

Incidence, pathogenesis, diagnostic strategy and indications for treatment. Aortic stenosis is a serious disease which should be diagnosed early because of the good operative results. For this reason it is important to be aware of the disease particularly in the elderly and in patients with a history of rheumatic fever (e.g. immigrants). The diagnosis should be suspected in the patient with one or more of the three following symptoms: dyspnoea, angina pectoris and syncopes, and who has a systolic ejection murmur at the base of the heart with transmission to the neck and a reduced or absent second heart sound. First priority next to routine examinations (stethoscopy, ECG, x-ray of the chest) is referral to echocardiography. The echocardiographic results in combination with the patient's history and the clinical examination almost always form a sufficient basis for the timing of the operation. Indications for operation are given.

Aortic Valve Stenosis↗
PubMed1993

Prodrugs of peptides. 18. Synthesis and evaluation of various esters of desmopressin (dDAVP).

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 were quantitatively converted to desmopressin by enzymatic hydrolysis in human plasma and rabbit liver homogenate. The esters with a straight side chain were rapidly hydrolyzed by alpha-chymotrypsin, but the sterically hindered pivalate ester proved more stable than desmopressin itself toward this proteolytic enzyme. All the esters were more lipophilic than desmopressin in terms of octanol-buffer partition coefficients. The transport of the compounds across confluent monolayers of Caco-2 cells was examined. No correlation between permeability and lipophilicity was found but the pivalate ester showed a markedly higher flux relative to desmopressin. It is concluded that appropriate esterification of desmopressin at its tyrosine group may be a potentially useful prodrug approach.

Biological Transport, Active↗
PubMed1993

Segmental differences in drug permeability, esterase activity and ketone reductase activity in the albino rabbit intestine.

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 isolated segments of the duodenum, jejunum, ileum, ascending colon, descending colon, and rectum. Esterase and ketone reductase activities were determined in homogenates of the above segments using timolol ester prodrugs and levobunolol as substrates, respectively. The results indicate that the hydrophilic beta adrenergic antagonists atenolol and sotalol and moderately lipophilic metoprolol penetrated all intestinal segments equally well, whereas moderately lipophilic timolol and lipophilic propranolol, levobunolol and betaxolol were better absorbed from the large than from the small intestinal segments. Changes in lipophilicity exerted a more pronounced effect on the penetration of beta adrenergic antagonists in the large than the small intestinal segments. A similar pattern existed for timolol prodrugs. In addition to segmental differences in drug permeability, segmental differences in esterase and ketone reductase activities also existed. The level of esterase and ketone reductase activities in the small intestinal segments was, on average, 12 times and 5 times higher, respectively, than in the large intestinal segments. The implication of the above findings is that segmental differences in drug permeability and metabolism must be considered in the design of oral drug delivery systems.

Adrenergic beta-Antagonists↗
PubMed1992

Stereoselective enzymatic hydrolysis of various ester prodrugs of ibuprofen and flurbiprofen in human plasma.

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 hydrolysis than the corresponding S-isomer. The difference in the hydrolysis rates between the enantiomeric forms ranged from a factor of 1.4 for the N,N-diethylglycolamide ester of ibuprofen to a factor of 50 and 25 for the 2-(1-imidazolyl)ethyl ester of ibuprofen and flurbiprofen, respectively. Therefore, enantioselective differences in plasma-catalyzed ester prodrug hydrolysis must be taken into account when evaluating prodrugs of racemic mixtures of chiral drugs.

Esters↗
PubMed1992

Relative bioavailability in man of noscapine administered in lozenges and mixture.

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 than that after administration of the drug as a mixture. It is concluded that the lozenges containing noscapine base may be a valuable alternative to the conventional noscapine hydrochloride mixture.

Adult↗
PubMed1992

Prodrugs of peptides. 19. Protection of the pyroglutamyl residue against pyroglutamyl aminopeptidase by N-acyloxymethylation and other means.

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 stability characteristics determined. The derivatives studied included phenoxycarbonyl, phthalidyl, hydroxymethyl and actoxymethyl derivatives, all formed at the pyroglutamyl NH-moiety. Whereas L-pyroglutamyl benzylamide was rapidly hydrolyzed by PAPase I, all the derivatives were resistant to cleavage by the enzyme. On the other hand, these derivatives, with the exception of the N-phenoxycarbonyl derivative, were readily converted to the parent pyroglutamyl benzylamide by spontaneous or plasma catalyzed hydrolysis, the half-lives of conversion in 80% human plasma being in the range 2.3-8.4 h. The major degradation reaction of the N-phenoxycarbonyl derivative in both buffer and plasma solutions was hydrolytic opening of the pyrrolidone ring. The pH-rate profiles for the degradation of the compounds in aqueous solution were obtained and both specific acid and base catalytic reactions as well as a spontaneous reaction were observed. The results suggest that N-phthalidylation, N-hydroxymethylation and N-acyloxymethylation of pyroglutamyl peptides may be useful prodrug approaches to protect such peptides against cleavage by pyroglutamyl aminopeptidase and hence to improve their delivery characteristics.

Humans↗
PubMed1992

N-substituted (aminomethyl)benzoate 21-esters of corticosteroids as water-soluble, solution-stable and biolabile prodrugs.

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 lives of hydrolysis in 80% plasma ranged from 8 min to 342 min, the rate being dependent on the structure of the amino group and its position relative to the ester moiety, as well as on the structure of the steroid. The esters showed maximal stability in aqueous solution at pH 3-4. From temperature-accelerated studies of the 3-[(4-methylpiperazin-1-yl)methyl)]benzoate ester of hydrocortisone, the shelf life of an aqueous solution (pH 4.0) of this ester was predicted to be 6 years at 25 degrees C. This estimated shelf life is not reduced by precipitation of the slightly soluble parent drug since the ester was shown to be capable of solubilizing hydrocortisone, possibly by self-micelization.

Adrenal Cortex Hormones↗
PubMed1992

Prodrugs of thiabendazole with increased water-solubility.

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.

Chromatography, High Pressure Liquid↗
PubMed1991

Carbamate ester prodrugs of dopaminergic compounds: synthesis, stability, and bioconversion.

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 highly unstable at pH 7.4 and 37 degrees C, the half-lives of hydrolysis being between 4 and 40 min. Plasma from various species catalyzed the hydrolysis of the carbamates. N,N-Disubstituted carbamates, on the other hand, were stable both in buffer and plasma solutions. They showed a very potent inhibition of butyrylcholinesterase (EC 3.1.1.8), but were less potent inhibitors of the specific erythrocyte acetylcholinesterase (EC 3.1.1.17). In vitro incubations of an N,N-dimethylsubstituted carbamate ester (10) with liver microsomes from mouse and rat showed an appreciable formation of the parent phenolic compound. This bioconversion is suggested to occur via an initial cytochrome P-450-catalyzed hydroxylation to give an N-hydroxymethyl derivative which spontaneously decomposes to the N-monomethylcarbamate. It is concluded that N,N-disubstituted carbamate esters may be potentially useful prodrugs for the 7-hydroxy-3-benzazepines, whereas N-monosubstituted carbamates appear to be too chemically and enzymatically labile.

Amino Acids↗
PubMed1991

Prodrugs of peptides. 9. Bioreversible N-alpha-hydroxyalkylation of the peptide bond to effect protection against carboxypeptidase or other proteolytic enzymes.

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 aldehyde but with vastly different rates. At pH 7.4 and 37 degrees C the half-lives of decomposition ranged from 4 min to 1500 hr. The structural factors influencing the stability included both steric and polar effects within the acyl and N-alpha-hydroxyalkyl moieties as well as within the amino acid attached to the N-alpha-hydroxyalkylated N-acyl amino acid. Whereas the N-benzyloxycarbonyl (Z) derivatives of the dipeptides Gly-L-Leu and Gly-L-Ala were readily hydrolyzed by carboxypeptidase A, the N-hydroxymethylated compounds, i.e., Z-Gly(CH2OH)-Leu and Z-Gly(CH2OH)-Ala, were resistant to cleavage by the enzyme as revealed by their similar rates of decomposition in the presence or absence of the enzyme at pH 7.4 and 37 degrees C. The results suggest that N-alpha-hydroxyalkylation of a peptide bond protects not only this bond but also an adjacent peptide bond against proteolytic cleavage. Since the N-alpha-hydroxyalkyl derivatives are readily bioreversible, undergoing spontaneous hydrolysis at physiological pH, this prodrug approach promises to overcome the enzymatic barrier to absorption of various peptides.

Alkylation↗
PubMed1991

Water-soluble, solution-stable, and biolabile N-substituted (aminomethyl)benzoate ester prodrugs of acyclovir.

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-dipropylaminomethyl)benzoate ester, a high stability in such solutions, allowing storage for several years. The esters combine these properties with a high susceptibility to undergo enzymatic hydrolysis in plasma. The half-lives of hydrolysis in 80% human plasma ranged from 0.8 to 57 min, the rate being highly dependent on the position (3 or 4) of the aminomethyl group relative to the ester moiety. All esters were more lipophilic than acyclovir in terms of octanol-pH 7.4 buffer partition coefficients. These properties make N-substituted (aminomethyl)-benzoate esters a promising new prodrug type for acyclovir to enhance its delivery characteristics.

Acyclovir↗
PubMed1991

Prodrugs of peptides. 11. Chemical and enzymatic hydrolysis kinetics of N-acyloxymethyl derivatives of a peptide-like bond.

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 process in the pH range 4-8.5, the half-lives being 1-11hr at 37 degrees C. The cause of this limited stability was suggested to be due to the occurrence of an elimination-addition mechanism involving a reactive N-acylminium ion intermediate. In alkaline solutions (pH greater than 10) the derivatives showed a normal ester stability. The ester group in the N-acyloxymethyl derivatives was readily hydrolyzed by plasma enzymes to yield the N-hydroxymethyl amide, which subsequently decomposed to the parent amide. The results obtained suggest that N-acyloxymethylation of a peptide bond may be a useful prodrug approach to obtain derivatives with varying lipophilicities and a ready ability to undergo conversion to the parent peptide in vivo. However, the stability of the derivatives in aqueous solutions is limited.

Chromatography, High Pressure Liquid↗
PubMed1991

Role of enzymatic lability in the corneal and conjunctival penetration of timolol ester prodrugs in the pigmented rabbit.

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 corneal and conjunctival penetration was determined using the isolated tissues in the modified Ussing chamber. The straight-chain alkyl and the unsubstituted cycloalkyl esters were hydrolyzed more rapidly than their corresponding branched-chain and substituted analogues as well as the aryl esters. The corneal and conjunctival penetration of all prodrugs, regardless of enzymatic lability, varied parabolically with lipophilicity. Moreover, the enzymatically more labile straight-chain alkyl esters penetrated the cornea and the conjunctiva more readily than the more stable branched-chain esters of comparable lipophilicity. Enzymatic lability is, therefore, an additional factor that should be considered in designing alkyl ester prodrugs with improved ocular drug delivery characteristics. Enzymatic lability does not, however, play as important a role as lipophilicity in the corneal and conjunctival penetration of cycloalkyl and aryl ester prodrugs.

Animals↗
PubMed1991

Prodrugs of peptides. 13. Stabilization of peptide amides against alpha-chymotrypsin by the prodrug approach.

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, in fact, accelerated the terminal amide bond cleavage, condensation with glyoxylic acid to produce peptidyl-alpha-hydroxyglycine derivatives and, to a minor extent, N-aminomethylation were found to improve the stability of the parent amides. Besides protecting the terminal, derivatized amide moiety toward cleavage by alpha-chymotrypsin, alpha-hydroxyglycine derivatization resulted in a significant protection, by a factor ranging from 5 to 75, of the internal peptide bond in various N-protected dipeptide amides. These derivatives are readily bioreversible, the conversion to the parent peptide or amino acid amide taking place either by spontaneous hydrolysis at physiological pH, as demonstrated for the N-Mannich bases, or by catalysis by plasma, as for peptidyl-alpha-hydroxyglycine derivatives.

Amides↗
PubMed1991

Corneal penetration of 5-fluorouracil and its improvement by prodrug derivatization in the albino rabbit: implication in glaucoma filtration surgery.

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 isolated albino rabbit cornea in the modified Ussing chamber. 5-FU and its prodrugs were analyzed by reversed phase HPLC. Corneal penetration of 5-FU was very poor due to its low lipophilicity and extensive metabolism during penetration. There was no conclusive evidence for carrier-mediated transport. The corneal epithelium offered the main diffusional and metabolic resistance. Prodrugs of 5-FU with improved lipophilicity dramatically increased the corneal penetration of 5-FU, suggesting that a much reduced dose of 5-FU could be used if corneal penetration and aqueous levels are necessary. It is anticipated that a similar lower dose of prodrug would be required should the prodrug also improve the diffusion of 5-FU across the sclera following subconjunctival injection. Whether dose reduction will lead to reduced corneal toxicity in glaucoma filtration surgery following topical or subconjunctival dosing is an interesting therapeutic opportunity that remains to be determined. In addition to enhancing 5-FU penetration, prodrugs also protected 5-FU from metabolism even though they were rapidly and quantitatively converted to 5-FU during penetration. Protection of 5-FU from metabolism in the cornea may be advantageous from the standpoint of sparing the cornea from toxicity caused by 5-FU, be it from topical or subconjunctival dosing.

Animals↗