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  • 1
    Electronic Resource
    Electronic Resource
    The interaction of erythromycin with theophylline (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 493-498 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; erythromycin ; drug interaction ; aminophylline ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the interaction of erythromycin with theophylline. We gave ten healthy volunteers theophylline as an intravenous loading dose (5 mg·kg−1) over 1 h, followed by a maintenance infusion (0.5 mg·kg−1·h−1) for 5 h. A second infusion of theophylline was given after 9 days of treatment with 1 g erythromycin base daily, and the concentrations of theophylline were determined during the infusion periods. The concentrations of erythromycin were measured for 8 h, after one week of treatment, and also after the last erythromycin dose, simultaneously with the second theophylline infusion. Concentrations within the therapeutic range were obtained with both drugs. A significant increase in both AUC and mean plasma concentrations of theophylline was seen during erythromycin treatment. The plasma clearance of theophylline was reduced in 9 of the 10 subjects. Renal clearance increased correspondingly, but the change was not statistically significant. Serum concentrations of erythromycin fell significantly, by more than 30%, with concurrent theophylline medication. We conclude that an interaction between theophylline and erythromycin, affecting both drugs, can be shown with concentrations of the drugs within the therapeutic range.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637676
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  • 2
    Electronic Resource
    Electronic Resource
    Absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin from different regions of the gastrointestinal tract in man (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 473-476 
    Details
    ISSN: 1432-1041
    Keywords: dDAVP ; bioavailability ; gastrointestinal tract ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP) from different regions of the gastrointestinal (GI) tract (stomach, duodenum, jejunum, ileum, colon, rectum) has been studied in 6 healthy, male volunteers aged 24 to 35 years, followed for 12 h after each drug administration. For i. v. administration the subjects received 4 μg dDAVP. For intestinal administration 400 μg dDAVP was directly applied to six distinct sites in the GI tract via two or four channel tubes with or without a distal occlusive balloon. Biological effects were assessed and plasma and urinary levels of dDAVP were measured using a specific, sensitive RIA. Urine osmolality remained elevated and diuresis decreased for 12 h following dDAVP administration irrespective of the site of application. After i. v. administration, the half-life of elimination of dDAVP was 60.0 min, plasma clearance 1.7 ml·min−1·kg−1, amount excreted in urine 2.0 μg and renal clearance was 0.8 ml·min−1·kg−1. The mean bioavailability (f) after gastric application was 0.19% (range 0.02–0.35%). f was 0.24% after duodenal application (range 0.04–0.62%), 0.19% after jejunal (range 0.01–0.41%), 0.03% after distal ileal (range 0.01–0.08%), 0.04% after proximal colonic (range 0.01–0.12%) and 0.04% after rectal (0.01–0.10%) application. The bioavailability was significantly higher in the three upper GI regions in comparison to the three lower regions. The bioavailability of dDAVP after gastric, duodenal and jejunal application was similar to that after swallowing a tablet in a previous study. Absorption from the ileum was lower than expected and no preferential site of absorption was found.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315546
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  • 3
    Electronic Resource
    Electronic Resource
    Inhibition of the Proteasome Reduces Transfer-Induced Diabetes in Nonobese Diabetic Mice (2004)
    Oxford, UK; Malden, USA : Blackwell Publishing Ltd/Inc.
    Scandinavian journal of immunology 60 (2004), S. 0 
    Details
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Inhibition of the 26S proteasome reduces the severity of several immune-mediated diseases. Here, we report that the proteasome also regulates transfer-induced diabetes in nonobese mice. Treatment of recipient mice with the proteasome inhibitor Nα-benzyloxycarbonyl-l-leucyl-l-leucyl-l-leucinal (MG132) resulted in a 76% reduction in transfer-induced diabetes. The closely related inhibitor carbobenzoxy-l-leucyl-l-leucinal that inhibits calpains but not the proteasome had no protective effect, suggesting that MG132 acted via inhibition of the proteasome. MG132 decreased proliferation of transferred T cells in the pancreatic lymph nodes in vivo and prevented their expansion in a dose-dependent manner in vitro, consistent with a direct effect by MG132 on the T cells. MG132 did not prevent migration of transferred T cells into the islets but reduced the number of mice with severe infiltration. We suggest that MG132 prevents transfer-induced diabetes by directly targeting the autoreactive T cells and lowering their diabetogenic potential.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.0300-9475.2004.01473.x
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  • 4
    Electronic Resource
    Electronic Resource
    Low Number of H-2Dd-Negative Haematopoietic Cells in Mixed Bone Marrow Chimeras Convey In Vivo Tolerance to H-2Dd-Negative Cells But Fail to Prevent Resistance to H-2Dd-Negative Leukaemia (2004)
    Oxford, UK; Malden , USA : Blackwell Science Ltd
    Scandinavian journal of immunology 59 (2004), S. 0 
    Details
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Natural killer (NK) cells kill cells lacking self major histocompatibility complex (MHC) class I. This missing self reactivity is beneficial in haploidentical bone marrow transplantations to cure leukaemia, in which donor-derived NK cells reject MHC disparate leukaemia cells and prevent relapse. To understand the role of NK cells in transplantation, we have studied NK cell tolerance in mice receiving mixed bone marrow transplants with limiting number of the MHC disparate component. Using an MHC class I (Dd) transgenic mouse model, we generated bone marrow chimeras carrying mixtures of Dd-positive and -negative cells. NK reactivity against Dd-negative cells (missing self) was assayed by outgrowth of lymphoma cells, stability of the chimerism in vivo and killing of Concanavalin A blasts in vitro. Up to 20% Dd-negative haematopoietic cells reduced, but did not abrogate, rejection of Dd-negative tumours and killing of Dd-negative T-cell blasts. In contrast, the ratios between Dd-positive and -negative cells were stable in vivo, suggesting tolerance to normal cells. Our data suggest that NK cell tolerance to normal cells and tumours in mixed MHC environments is differentially regulated, tolerance to normal cells being more easily induced. These results are important in relation to the role of NK cells in antileukaemic reactions after bone marrow transplantation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.0300-9475.2004.01363.x
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  • 5
    Electronic Resource
    Electronic Resource
    Bioavailability of 1-deamino-8-D-arginine vasopressin with an enzyme inhibitor (aprotinin) from the small intestine in healthy volunteers (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 491-495 
    Details
    ISSN: 1432-1041
    Keywords: Key words Aprotinin ; Arginine vasopressin; bioavailability ; dDAVP ; enzyme inhibitor ; gastrointestinal tract ; healthy volunteer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP), with and without an enzyme inhibitor, was studied in six healthy, male volunteers aged 19–34 years, followed for 8 h after each drug administration. Methods: For i.v. administration the subjects received 4 μg dDAVP. For intestinal administration 500 μg dDAVP was administered directly, in two separate sessions, in the first part of the duodenum via a triple-lumen channel tube. In one session a solution of isotonic polyethylene glycol (PEG) was given as a continuous enteral perfusion. In the other session a solution of PEG and aprotinin was administered enterally at the constant rate of 5 ml⋅min−1 for 4 h. Plasma dDAVP was measured using a specific, sensitive radioimmunoassay and intestinal juice was collected for measurement of lipase, chymotrypsin and pH every 30 min for 5 h. Results: The intestinal chymotrypsin activity was decreased after perfusion of aprotinin while the lipase activity was not modified. After i.v. administration, the half-life of elimination of dDAVP was 1.56 h and plasma clearance 1.24 ml⋅min⋅kg−1. The mean bioavailability after duodenal administration of dDAVP + aprotinin was 0.46% compared with 0.09% after duodenal administration of dDAVP alone. The bioavailability of dDAVP after direct duodenal administration of an aqueous solution was similar to that after swallowing a tablet in a previous study and increased 5 times when given together with a perfusion of an enzyme inhibitor.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050146
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  • 6
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and antidiuretic effect of a new vasopressin analogue (F992) in overhydrated male volunteers (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 293-298 
    Details
    ISSN: 1432-1041
    Keywords: Key words Vasopressin analogue F992 pharmacokinetics ; Antidiuresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The aim of the present study was to study the pharmacokinetics, the antidiuretic effects and the safety of [D-Phe2, Thi3, α-Me-Abu4, Hyp7, D-Arg8]-dC1-vasopressin, a new antidiuretic peptide (F992, Ferring, Sweden), administered as intravenous infusion to orally overhydrated male volunteers. Methods: Eight healthy male volunteers participated in this open study consisting of two parts: a dose titration study and a safety study. In the dose titration study ascending doses of F992 were administered to volunteers in pairs in order to find a dose that within 1 h after the infusion, in both subjects, caused a reduction of the urine flow rate to below 5 ml · min−1 (target dose). Subsequently, this target dose was administered to all volunteers. In the safety study the target dose was doubled and given to all volunteers. On each study occasion, in both study parts, the subjects were orally overhydrated with water. F992 was administered as i.v. infusion approximately 1.5 h after the start of the hydration procedure. Throughout the study days, blood was sampled for determination of plasma concentrations of F992 and for safety evaluation. Urine was collected at intervals in order to estimate flow rate and osmolality. Results: The target dose was found to be 4.0 μg as this dose fulfilled the criteria regarding antidiuretic effect, consequently 8.0 μg was administered to all subjects in the safety study. After infusion of 4.0 and 8.0 μg, the median half-lives of elimination were 4.72 (range 3.99–6.53) h and 3.85 (range 3.04–11.08) h, respectively. The plasma clearance and the volume of distribution at steady state were estimated to be 0.88 (SD 0.24) ml · min−1 · kg−1 and 326 (SD 68) ml · kg−1 after infusion of 4 μg. After the highest dose (8 μg), the corresponding estimates were 0.86 (SD 0.32) ml · min−1 · kg−1 and 299 (SD 81) ml · kg−1, respectively. Significantly (P = 0.033) different maximum mean urine osmolalities were produced after infusion of 4.0 and 8.0 μg of F992 (534 (SD 318) vs 732 (SD 189) mOsmol · kg−1). The median times to reach these values showed some tendency to be longer for the highest dose, however statistical significance was not reached. No serious adverse events were observed during the study. Conclusion: We found it safe to administer F992 as infusion to overhydrated male volunteers. The results suggest that F992 has a longer half-life and a lower potency than the widely used peptide desmopressin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050631
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  • 7
    Electronic Resource
    Electronic Resource
    Changes in gastrointestinal motility influence the absorption of desmopressin (1999)
    Springer
    European journal of clinical pharmacology 55 (1999), S. 305-309 
    Details
    ISSN: 1432-1041
    Keywords: Key words Gastrointestinal motility ; Absorption ; Desmopressin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The antidiuretic effect of desmopressin is widely utilized in the treatment of neurogenic diabetes insipidus and nocturnal enuresis in children. The objective of the present study was to assess how changes in gastrointestinal motility, induced by erythromycin and loperamide, influence the pharmacokinetics of orally administered desmopressin. Methods: This study was conducted using an open randomized, three-period, three-treatment design in 18 healthy subjects. On each study day a single oral dose of 400 μg desmopressin was administered in the morning. The desmopressin dose was either given alone (reference) or after pretreatment with either loperamide tablets (4 mg at −24, −12 h and −1 h) or erythromycin capsules (250 mg q.i.d, with the first dose in the morning 3 days before the study day and the last dose at −1 h). On each study day, blood was sampled up to 8 h after dosing for assessment of desmopressin concentration. Results: Compared with administration of 400 μg of desmopressin alone, pretreatment with loperamide produced significantly (P 〈 0.05) altered pharmacokinetics of desmopressin as the endpoints; area under the curve up to infinity (AUC), area up to the last determinable plasma concentration (AUCt) and maximum plasma concentration (Cmax) increased 3.1-fold (95% CI 2.3–4.2), 3.2 (2.3–4.4) and 2.3 (1.6–3.2), respectively. Although the estimates were lower, pretreatment with erythromycin did not result in any significant changes in these endpoints. There were no significant changes observed between the three treatments regarding the terminal elimination half-life (t1/2). However, significant (P 〈 0.05) changes in the time to reach Cmax (tmax) values (median and range) were observed as, compared with administration of desmopressin alone (1.3 h and 0.5–4.0), it was longer after pretreatment with loperamide (2.0 h and 0.5–3.0) and shorter following pretreatment with erythromycin (0.9 h and 0.5–1.3). Conclusion: Presumably due to slower gastrointestinal motility, pretreatment with loperamide significantly increases the gastrointestinal absorption of desmopressin. Except for a shortening of tmax, pretreatment with erythromycin did not significantly influence absorption of the drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050633
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