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Biomedical subjects

B Ekström

Publications and source records attributed to B Ekström.

At least 19 recordsLinked to original sources

Urodynamic and other effects of tolterodine: a novel antimuscarinic drug for the treatment of detrusor overactivity.

Tolterodine, a novel compound intended for treatment of urgency and urge incontinence, has been characterized as a potent muscarinic receptor antagonist in pharmacological in vitro and in vivo studies. In cats, tolerodine was shown to reduce bladder pressure at doses significantly lower than those affecting salivation. To predict clinical effectiveness, an open pilot study was performed in healthy male volunteers. Efficacy was measured by cystometry and by spontaneously reported effects after administration of a single oral dose of tolterodine, 6.4 mg, given as a water solution. Tolterodine had distinct inhibitory effects on urinary bladder function, both at 1 and 5 hours post-dose. At 1 hour, but not at 5 hours post-dose tolterodine also significantly reduced stimulated salvation. In addition to the objectively demonstrated changes in urodynamic parameters, most volunteers experienced voiding difficulties. No significant changes in blood pressure, heart rate, or near point of accommodation were registered. Tolterodine, in the dosage used, was both objectively and subjectively shown to exert a marked inhibitory effect on micturition in healthy subjects, and the data suggest a more pronounced effect on bladder function than on salivation.

Adult

Intravesical instillation of terodiline--an in vivo study of drug absorption in rabbit and man.

The absorption of intravesically administered terodiline was investigated in 8 healthy volunteers (10(-4)) and in 33 rabbits (10(-4)) M., 4 X 10(-4) M. and 1.6 X 10(-3) M.). In the humans, the amount of drug retained and the serum concentration were registered. In the rabbits, the influence of drug concentration, pH (5 and 9.2) and volume (5 and 20 ml.) were evaluated. Liquid scintigraphy of the bladder wall and of serum and tissue samples from striated muscle, kidney and liver was performed. Further, autoradiography of the bladder wall and calculation of drug retention were done. In the humans, 20 +/- 5% of the administered terodiline dose was retained in the body. Clinically significant serum concentrations were not detected. In the rabbits, 21 +/- 4% of the drug was retained with the pH = 5 terodiline solution as compared with 64 +/- 3% with the pH = 9.2 solution. With increasing terodiline concentrations, drug retention increased, as did the tissue and serum activities. At a given concentration, the total amount of drug retained increased with a larger volume. The drug gradient between the bladder muscle layer and serum was of a magnitude of about 100, independent of the drug concentration within the muscle layer. It is concluded that the pH and concentration of the solution are factors of major importance for the amount of terodiline absorbed from the bladder. Compared with the one obtainable by systemic drug administration, the large gradient between the bladder muscle and the serum is conspicuous, and may be of clinical interest.

Administration, Intravesical

Urodynamic effects of intravesical instillation of atropine and phentolamine in patients with detrusor hyperactivity.

The effects of intravesical instillation of atropine (10(-6) M) and phentolamine (10(-6) M) on urodynamic parameters were investigated in patients with detrusor hyperactivity of neurogenic or non-neurogenic origin. A modified cystometric technique with slow intermittent filling was used. The reproducibility of the investigative procedure was first verified in 17 patients. Eighteen patients, 12 with detrusor hyperreflexia and 6 with detrusor instability, were then investigated with atropine and 17 patients, 11 with detrusor hyperreflexia and 6 with detrusor instability, were investigated with phentolamine. In individual patients clinically relevant improvements, such as an increased bladder capacity and a decreased detrusor pressure, were found. Five/12 neurogenic and 1/6 non-neurogenic patients responded to instillation of atropine. Five/11 neurogenic but none of the non-neurogenic patients responded to phentolamine. In the neurogenic group phentolamine caused an increase of the bladder capacity from 247 +/- 57 ml. to 378 +/- 57 ml. (p < 0.05). It is suggested that the different sensitivities to intravesical drug administration in patients with detrusor hyperreflexia and detrusor instability can be explained by pathophysiological differences and concluded that intravesical instillation of drugs may be of therapeutic value in selected groups of patients.

Administration, Intravesical

Pharmacokinetics of R(+)-terodiline given intravenously and orally to healthy volunteers.

(+)-Terodiline was given orally (25 mg) and intravenously (12.5 mg) to eight healthy volunteers. The pharmacokinetics of (+)-terodiline could be described by a one compartment model. The lag time of absorption was 0.6 +/- 0.5 hr (mean +/- S.D.), the absorption half-life 0.9 +/- 0.5 hr, the time to maximum serum concentration 5.6 +/- 2.2 hr and the corresponding maximum serum concentration 62 +/- 22 micrograms/l. The volume of distribution was found to be 372 +/- 84 1, the systemic clearance 86 +/- 29 ml/min., the mean residence time 81 +/- 38 hr and the observed terminal half-life of elimination 56 +/- 26 hr. The urinary excretion of the intravenous dose was 12 +/- 6% and the renal clearance 10 +/- 5 ml/min. The bioavailability of (+)-terodiline was 93 +/- 19%. The present results indicate that (+)-terodiline as well as the racemate can be characterized as low clearance long half-life drugs. One subject was a poor hydroxylator of debrisoquine and exhibited a 3-fold decrease in clearance and increase in half-life of (+)-terodiline relative to extensive metabolizers. Observed pharmacological effects were mild accomodation disturbances and dry mouth, i.e. the same effects as those that may be seen at a corresponding dose of terodiline given as a racemic mixture.

Absorption

Urodynamic effects of intravesical instillation of terodiline in healthy volunteers and in patients with detrusor hyperactivity.

The effects of intravesical instillation of terodiline on urodynamic parameters were investigated in 8 healthy volunteers (10(-4) M.) and in 34 patients with detrusor hyperactivity (10(-5) M.) of neurogenic (22) or nonneurogenic (12) origin. The volunteers were investigated with conventional medium-fill cystometry, while in the patients a modified cystometric technique with slow intermittent filling was used. The reproducibility of the procedure was verified in 17 patients. Instillation of terodiline had no effect on the normal bladders nor were any improvements found in the nonneurogenic patients. In 12 patients in the neurogenic group treated with terodiline instillation the bladder capacity increased significantly (p < 0.05) from 289 +/- 32 to 413 +/- 55 ml. Within this group 5 patients were responders. It is suggested that pathophysiological changes may explain the difference between the neurogenic and nonneurogenic groups, and that the number of responders within the neurogenic group may be increased by an optimal drug preparation and increased dosage. Intravesical administration of terodiline may offer an alternative treatment in selected patients with detrusor hyperreflexia.

Administration, Intravesical

Intravesical instillation of drugs in patients with detrusor hyperactivity.

Intravesical administration of drugs may inhibit detrusor hyperactivity. Intravesical drug administration might be clinically useful in patients with detrusor hyperactivity, particularly in patients with neurogenic etiology using CIC. The therapeutic usefulness has to be documented in controlled studies. The mechanisms of action and the potency of the individual substances can not be decided from the present investigations. However, no finding contradicts that the known pharmacological properties of the drugs used are responsible for the effects noted. The different responsiveness to intravesical drugs between patients with neurogenic and non-neurogenic etiology might be due to pathophysiological differences. By intravesical administration of drugs the tissue concentration obtainable within the bladder wall is higher than the one obtainable by systemic administration. The optimal relation between tissue and serum concentrations can be achieved by a careful preparation of the drug solution and by titration of the dose. No side effects were found in the studies and no clinically significant side effects have been reported by other investigators. The risk of late side effects is unknown. The serum concentrations found in man and rabbit, after intravesical instillation of terodiline, indicate that by this route of administration terodiline may be safely used, in spite of the side effects reported at systemic administration. For evaluation of the diagnostic usefulness further documentation of the mechanisms of action and of the pathophysiology are needed.

Administration, Intravesical

Effects of intravesical instillation of verapamil in patients with detrusor hyperactivity.

The effects of verapamil instilled intravesically were investigated in patients with detrusor hyperactivity of neurogenic and non-neurogenic origin. An intermittent, well reproducible cystometric technique with stepwise infusion of fluid was used. Verapamil produced a significant increase of the bladder capacity in patients with detrusor hyperreflexia, but not in patients with detrusor instability. The drug had no significant influence on any other cystometric parameter. It is suggested that pathophysiological differences between hyperactivity of neurogenic and non-neurogenic origin may be responsible for the difference observed. The possible diagnostic and/or therapeutic importance of the present findings remains to be established.

Administration, Intravesical

Lipolysis of polyenoic fatty acid esters of human chylomicrons by lipoprotein lipase.

Human chylomicrons, obtained from chylous pleural fluid of a patient with mesothelioma, were incubated with bovine milk lipoprotein lipase. No difference in the release of different C16-C18 fatty acids as unesterified fatty acids, or in their appearance in diacylglycerols, was observed. The rate of lipolysis of arachidonic (20:4), and eicosapentaenoic (20:5) acid ester bonds of chylomicron triacylglycerols was slower, and a larger proportion of these fatty acids accumulated in mono- and diacylglycerols. The hydrolysis pattern for docosahexaenoic acid (22:6) was intermediary between that of the C16-C18 fatty acids and that of 20:4 and 20:5. The data suggest that the presence of a double bond at position 5 in the eicosanoid precursors may be important for the rate of lipolysis. The relative resistance of the 20:4- and 20:5- esters of chylomicrons to lipoprotein lipase may be important for the tissue distribution of these fatty acids.

Arachidonic Acid

Fast horizontal electrophoresis. II. Development of fast automated staining procedures using PhastSystem.

The development of equipment for fast automated staining is described. It is possible to handle staining procedures with up to 20 steps and nine different solutions. To increase the reaction rate in the reaction chamber, the gels are rotated and high temperatures are used. The temperature in the reaction chamber is controlled between room temperature and 50 degrees C. Increased temperature, above 20 degrees C, generally results in faster staining and destaining. However, some reactions proceed better at a low temperature, including fixation of proteins with TCA, and the development step in silver staining, where increased temperatures cause a high background stain. Silver staining using acidic silver nitrate solution is preferred, due to easy preparation and good storage stability of the reagents. This method also causes little precipitation of silver on the walls of the reaction chamber. Silver staining is accomplished within one hour. Staining with PhastGel Blue is accomplished within 30 min.

Automation

Actions of terodiline, its isomers and main metabolite on isolated detrusor muscle from rabbit and man.

The effects of racemic terodiline on isolated detrusor preparations from rabbit and man were compared with those of its (+)- and (-)-isomers, and with those of its main metabolite, parahydroxy-terodiline. Concentration-response (c-r) relations for carbachol and frequency-response relations for electrical stimulation were determined before and after addition of drugs. In preparations from both rabbit and man, all the drugs tested concentration-dependently shifted the c-r curve for carbachol to the right. (+)-Terodiline was more potent than (+/-)-terodiline, whereas (-)-terodiline and parahydroxy-terodiline were less potent. All drugs in concentrations greater than 10(-6) M had a non-competitive effect, depressing the maximum of the carbachol contraction. All drugs had a depressant effect on electrically evoked contractions. (+)-Terodiline was as effective (rabbit) or more effective (man) than (+/-)-terodiline, whereas (-)-terodiline and parahydroxy-terodiline were less effective. It is concluded that (+)-terodiline contributes to a main part of the detrusor effects of the racemate, and that part of this action is anticholinergic. Parahydroxy-terodiline had a profile of action similar to that of (+/-) terodiline, but its potency was low. Since it is present in plasma in low concentrations, its contribution to the clinical effects of terodiline is probably small. (+)-Terodiline may have a therapeutic potential.

Animals

Design and synthesis of peptide derivatives of a 3-deoxy-D-manno-2-octulosonic acid (KDO) analogue as novel antibacterial agents acting upon lipopolysaccharide biosynthesis.

On the basis of the knowledge that the amino acid 3 (8-amino-2,6-anhydro-3,8-dideoxy-D-glycero-D-talo-octonic acid) is a potent inhibitor of 3-deoxy-manno-octulosonate cytidylyltransferase, attempts were made to design derivatives that would act as antibacterials against Gram-negative bacteria by inhibiting lipopolysaccharide biosynthesis. Compound 3 and the derivatives 15 and 16 containing an additional amino acid were not lethal to bacteria. However, compounds 17-22, which contain a N-terminally linked dipeptide, exhibited good antibacterial activity in vitro on testing against strains of the Gram-negative bacteria Escherichia coli and Salmonella typhimurium. They have no activity against Gram-positive bacteria such as Staphylococcus aureus.

Anti-Bacterial Agents

Effect of high dose corticosteroids alone or combined with other drugs on survival in septic shock.

The effect of high dose corticosteroids on survival has been studied in a limited number of canine septic shock models which are reviewed in this presentation. Following injection of live bacteria neither methylprednisolone, nor gentamicin but a combination improved survival. Methylprednisolone increased survival following a slow but not a bolus infusion of endotoxin. In a recent study the effects of short term treatment with methylprednisolone, naloxone and ibuprofen were studied in endotoxin shock. All control animals died within 36 hours. Five of 9 dogs receiving the combination methylprednisolone, naloxone and ibuprofen were permanent survivors. The combined treatment with methylprednisolone and ibuprofen also increased survival. Dogs treated with methylprednisolone alone did not differ significantly from controls. It is concluded that methylprednisolone alone has no significant effect on survival in septic shock, but seems to be an important therapeutic factor to achieve increased survival.

Animals

Differences in retention behavior between small and large molecules in ion-exchange chromatography and reversed-phase chromatography.

The retention (k') for various biomolecules was studied as a function of the mobile phase composition in reversed-phase chromatography (RPC) and ion-exchange chromatography (IEC). The "elution window" (EW) for a molecule is defined as the mobile phase composition in which 1 less than k' less than 10. The following relations were verified: (i) EW(RPC) less than EW(IEC), and (ii) EW(large Mr) less than EW(small Mr). The results support the theory that in both RPC and IEC larger molecules interact with the stationary phase by multiple-site binding. The results are used to explain why, in both RPC and IEC, larger molecules are best separated on short columns using gradient elution while smaller molecules often require longer columns and isocratic conditions.

Chromatography

Basic design of beta-lactam antibiotics: penams and analogues and monocyclic beta-lactams.

Improved microbiological and chemical techniques have resulted in the development of a range of new beta-lactam antibiotics with valuable clinical properties. The work on semi-synthetic penicillins demonstrated that by alteration of the side chain in the 6-position of the penam structure it was possible to significantly affect the antibacterial activity of the compounds and their stability against degradation by acids and beta-lactamases. Esterification of the carboxyl group in the 3-position may improve the pharmacokinetic properties of the compounds whereas substitution in the bicyclic penam structure may give compounds with strong inhibitory action against beta-lactamases. Penems are available by chemical synthesis and may have potent antibacterial activity and good stability against beta-lactamases. Carbapenems can be obtained microbiologically and chemically. The latter, include compounds which have high and broad antibacterial activity as well as those which are potent inhibitors of beta-lactamases. Many of the compounds are, however, chemically rather labile and may also be degraded by a dehydropeptidase present in the kidneys. Clavulanic acid is a microbial oxapenam with modest antibacterial activity but potent inhibitory activity against beta-lactamases. Two types of monocyclic beta-lactams with antibacterial properties, the nocardicins and the monobactams, have so far been found to be produced by microorganisms. They have modest in vitro activity, but at least in case of the monobactams it has been possible to obtain compounds by chemical derivatization with high activity against Gram-negative bacteria and with high stability against beta-lactamases.

Anti-Bacterial Agents

Increased survival of endotoxin-injected dogs treated with methylprednisolone, naloxone, and ibuprofen.

The effects of methylprednisolone, naloxone, and ibuprofen--alone and in various combinations--on survival, blood pressure, hematocrit, and peripheral platelet and white blood cell counts were studied in a canine Escherichia coli endotoxin LD100 shock model. Treatment was started 10 minutes after shock induction. The dogs were kept on a respirator and given intravenous fluids for 4 hours, then disconnected from the respirator and allowed to recover. Dogs surviving 7 days were considered permanent survivors. All control animals died within 36 hours. Five of nine dogs receiving a combined treatment of methylprednisolone, naloxone, and ibuprofen were permanent survivors and showed no macroscopic abnormalities when autopsied. The combined treatment with methylprednisolone and ibuprofen also increased survival. Mortality was delayed in animals treated with methylprednisolone and naloxone. Dogs receiving ibuprofen, a cyclooxygenase inhibitor, had a rapid reversal of hypotension. Hematocrit and platelet counts were similar in all groups. The combined treatment caused an increase in the recovery rate of white blood cells.

Animals

Isolation and characteristics of human urinary sialoglycoproteins.

Three sialoglycoproteins (S1, S2, and S3) have been isolated from normal human urine by ultrafiltration, zone electrophoresis, gel chromatography, and ion-exchange chromatography. The average yields per litre of urine were 0.39 mg (S1), 0.40 mg (S2), and 1.9 mg (S3). The isolated substances were homogeneous on ultracentrifugation both at neutral and acid pH with sedimentation coefficients of 3.6 S (S1), 2.4S (S2), and 0.93S (S3). Equilibrium ultracentrifugation gave molecular weights of 77900 (S1), 37000 (S2), and 5300 (S3). All three components were rich in carbohydrate (64 to 76%) and contained 28 to 35% of sialic acid. Alkaline borohydride degradation of component S3 yielded two sialylated oligosaccharides which were partially characterized. The origin of the isolated substances is unknown. The molecular size of S3 (Stokes' radius of 2.0 nm) is compatible with passage from the blood by glomerular filtration whereas the size of S1 (Stokes' radius of 6.5 nm) would suggest a renal origin.

Chemical Phenomena