| 1. |
- Andersen, Jan Terje, et al.
(författare)
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Extending Half-life by Indirect Targeting of the Neonatal Fc Receptor (FcRn) Using a Minimal Albumin Binding Domain
- 2011
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 286:7, s. 5234-5241
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Tidskriftsartikel (refereegranskat)abstract
- The therapeutic and diagnostic efficiency of engineered small proteins, peptides, and chemical drug candidates is hampered by short in vivo serum half-life. Thus, strategies to tailor their biodistribution and serum persistence are highly needed. An attractive approach is to take advantage of the exceptionally long circulation half-life of serum albumin or IgG, which is attributed to a pH-dependent interaction with the neonatal Fc receptor (FcRn) rescuing these proteins from intracellular degradation. Here, we present molecular evidence that a minimal albumin binding domain (ABD) derived from streptococcal protein G can be used for efficient half-life extension by indirect targeting of FcRn. We show that ABD, and ABD recombinantly fused to an Affibody molecule, in complex with albumin does not interfere with the strictly pH-dependent FcRn-albumin binding kinetics. The same result was obtained in the presence of IgG. An in vivo study performed in rat confirmed that the clinically relevant human epidermal growth factor 2 (HER2)-targeting Affibody molecule fused to ABD has a similar half-life and biodistribution profile as serum albumin. The proof-of-concept described may be broadly applicable to extend the in vivo half-life of short lived biological or chemical drugs ultimately resulting in enhanced therapeutic or diagnostic efficiency, a more favorable dosing regimen, and improved patient compliance.
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| 2. |
- Andersson, Karl-Erik, et al.
(författare)
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CNS involvement in overactive bladder: pathophysiology and opportunities for pharmacological intervention.
- 2003
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Ingår i: Drugs. - 0012-6667. ; 63:23, s. 2595-2611
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Forskningsöversikt (refereegranskat)abstract
- The pathophysiology of overactive bladder (OAB) syndrome is complex, and involves both peripheral and CNS factors. Several CNS disorders are associated with OAB, e.g. stroke, spinal cord injury, Parkinson’s disease and multiple sclerosis, and in each disorder the pathophysiology of OAB can be multifactorial. Irrespective of cause or pathophysiology of OAB, antimuscarinic drugs are the first line of pharmacological treatment. However, adverse effects and limited efficacy makes alternative therapeutic principles desirable. Most alternative drugs used for the treatment of OAB have a peripheral site of action, mainly affecting efferent or afferent neurotransmission or the detrusor muscle itself. New targets for pharmacological intervention may be found in the CNS. Several CNS transmitters/transmitter systems are known to be involved in micturition control, but few drugs with a defined CNS site of action (e.g. baclofen, imipramine and duloxetine) have been used for the treatment of voiding disorders. GABA, glutamate, opioid, serotonin, noradrenaline (norepinephrine), and dopamine receptors and mechanisms are known to influence micturition, and drugs influencing these systems could potentially be developed for the treatment of OAB. Preclinical studies in different animal models have shown that modulation of normal micturition and detrusor overactivity by drugs acting within the spinal cord or supraspinally is possible. Promising results have been obtained in such models, e.g. with drugs interfering with GABA mechanisms, serotonin 5-HT1A receptors, mu-opioid receptors and alpha-adrenoreceptors. However, considering the limited predictability of existing animal models for efficacy in humans, positive proof of concept studies in humans are mandatory. Such studies are scarce and further investigations are needed.
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| 3. |
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| 4. |
- Elmståhl, Barbara, et al.
(författare)
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Iodixanol 320 results in better renal tolerance and radiodensity than do gadolinium-based contrast media: Arteriography in ischemic porcine kidneys
- 2008
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Ingår i: Radiology. - : Radiological Society of North America (RSNA). - 1527-1315 .- 0033-8419. ; 247:1, s. 88-97
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To prospectively compare nephrotoxicity and radiodensity of plasma hyperosmotic gadolinium chelates (attenuation-osmotic ratio of 1: 1) with those of plasma iso-osmotic iodine-based contrast media (attenuation-osmotic ratio of 3: 1 or 6: 1) after renal arteriography in ischemic porcine kidneys. Materials and Methods: The local animal care committee approved this study. The following contrast media were used: (a) iodixanol (150 mg of iodine per milliliter and 320 mg I/mL, 0.29 osm/kg H2O), (b) iopromide (150 mg I/mL, 0.34 osm/kg), (c) 0.5 mol/L gadodiamide (0.78 osm/kg), and (d) 1.0 mol/L gadobutrol (1.6 osm/kg). After left-sided nephrectomy, contrast media (3 mL per kilogram of body weight) were injected (20 mL/min) in a noncrossover design into the right renal artery of pigs during a 10-minute ischemic period. There were eight pigs in each group and one group for each contrast medium. We compared histomorphology, radiographic contrast medium excretion, subjective radiodensity of nephrograms (70 kVp) at the end of injection, and contrast medium plasma half-life elimination times 1-3 hours after injection. Longer elimination times resulted in lower glomerular filtration rates. Results: Gadobutrol caused extensive tubular necrosis and moderate glomerular necrosis; gadodiamide and iopromide, minimal to mild tubular necrosis; and iodixanol, no necrosis. Gadobutrol was the only contrast medium to show no sign of excretion, and its plasma half-life elimination time (median, 1103 minutes; P = .001) was significantly longer than that of other contrast agents. Gadodiamide had a significantly longer plasma half-life elimination time (median, 209 minutes; P = .01) than did iodine-based contrast media (median, 136-142 minutes). The 320 mg I/mL dose of iodixanol had the highest radiodensity, whereas gadodiamide had the lowest radiodensity. The radiodensity of the 320 mg I/mL dose of iodixanol was greater than that of the 150 mg I/mL dose of iodixanol, which was equal to the radiodensities of the 150 mg I/mL dose of iopromide and 1.0 mol/L gadobutrol, which in turn were greater than that of 0.5 mol/L gadodiamide. Conclusion: Plasma iso-osmotic iodine-based contrast media used at commercially available concentrations have superior attenuation and nephrotoxic profiles compared with equal volumes of hyperosmotic nonionic 0.5-1.0 mol/L gadolinium-based contrast media when performing renal arteriographic procedures. (c) RSNA, 2008.
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| 5. |
- Orlova, Anna, et al.
(författare)
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Synthetic affibody molecules : a novel class of affinity ligands for molecular imaging of HER2-expressing malignant tumors
- 2007
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 67:5, s. 2178-2186
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Tidskriftsartikel (refereegranskat)abstract
- The Affibody molecule Z(HER2:342-pep2), site-specifically and homogeneously conjugated with a 1,4,7,10-tetra-azacylododecane-N,N',N'',N'''-tetraacetic acid (DOTA) chelator, was produced in a single chemical process by peptide synthesis. DOTA-Z(HER2:342-pep2) folds spontaneously and binds HER2 with 65 pmol/L affinity. Efficient radiolabeling with >95% incorporation of (111)In was achieved within 30 min at low (room temperature) and high temperatures (up to 90 degrees C). Tumor uptake of (111)In-DOTA-Z(HER2:342-pep2) was specific for HER2-positive xenografts. A high tumor uptake of 23% injected activity per gram tissue, a tumor-to-blood ratio of >7.5, and high-contrast gamma camera images were obtained already 1 h after injection. Pretreatment with Herceptin did not interfere with tumor targeting, whereas degradation of HER2 using the heat shock protein 90 inhibitor 17-allylamino-geldanamycin before administration of (111)In-DOTA-Z(HER2:342-pep2) obliterated the tumor image. The present results show that radiolabeled synthetic DOTA-Z(HER2:342-pep2) has the potential to become a clinically useful radiopharmaceutical for in vivo molecular imaging of HER2-expressing carcinomas.
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| 6. |
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| 7. |
- Pehrson, Rikard
(författare)
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Central nervous system targets for micturition control
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Normal urine storage and bladder emptying are controlled by the central (CNS) as well as the peripheral nervous system. Dysfunction of these mechanisms can lead to urinary incontinence. Urinary tract dysfunctions have symptomatically been treated mainly with drugs acting peripherally. However, in the CNS, drug targets for pharmacological intervention may be found. The present study deals with effects on micturition of drugs active on receptors for GABA, 5-HT and enkephalins. Rat models of normal and dysfunctional micturition were used. Reuptake inhibition of GABA (tiagabine), as well as stimulation of GABAb receptors (baclofen) inhibited micturition. The sites of actions were the spinal cord and/or brain. Tiagabine depressed neurogenic contractions and acetylcholine release in rat detrusor strips. Blockade of GABAb receptors (CGP62349) increased the frequency of micturitions. Stimulation of receptors for 5-HT, in particular the 5-HT1a receptor subtype, facilitated micturition. Blockade of this receptor subtype (NAD-299 and WAY100635) increased bladder storage capacity via a supraspinal mechanism. Tramadol, a mixed opioid receptor agonist and reuptake inhibitor of 5-HT and noradrenaline, in analgesic doses increased bladder storage capacity, without impairing bladder emptying. The effect was dependent on the (+)-enantiomer, which stimulates m-opioid receptors and inhibits 5-HT reuptake. Tramadol and GABAb receptor stimulation reversed detrusor overactivity due to C-fibre activation in the bladder. Activation of CNS dopamine receptors, as well as experimental cerebral-infarction, induced detrusor overactivity which could be reversed by tramadol. Drugs influencing the CNS micturition control may offer new possibilities to treat lower urinary tract disorders, including detrusor overactivity.
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| 8. |
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| 9. |
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| 10. |
- Pehrson, Rikard, et al.
(författare)
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Effects of tiagabine, a gamma-aminobutyric acid re-uptake inhibitor, on normal rat bladder function.
- 2002
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Ingår i: Journal of Urology. - 1527-3792. ; 167:5, s. 2241-2246
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Previous reports have demonstrated the inhibitory effect of exogenous gamma-aminobutyric acid (GABA) on micturition. In the current study we tested whether tiagabine (Sanofi Synthelab., Newcastle-upon Tyne, United Kingdom), a GABA re-uptake inhibitor increasing endogenous GABA concentrations, would affect micturition in awake rats or influence rat detrusor contraction in vitro. MATERIALS AND METHODS: Nonanesthetized female Sprague-Dawley rats underwent cystometric investigation in a metabolic cage. Micturition was stimulated by infusing saline intravesically. Micturition parameters were recorded and compared before and after drug administration. In vitro the effects of tiagabine on electrical and carbachol induced contractions in bladder strips were investigated. Furthermore, it was studied whether tiagabine interfered with electrically induced release of acetylcholine. RESULTS: Intravenous administration of 5 and 20 mg. kg.-1 tiagabine in 7 and 9 rats decreased micturition pressure a mean plus or minus standard error of mean of 21% +/- 11% and 42% +/- 9%, and decreased voided volume a mean of 31% +/- 9% and 33% +/- 9%, respectively. At 20 mg. kg.-1 tiagabine intravenously increased post-void residual volume a mean of 300% +/- 120% and decreased bladder capacity a mean of 14% +/- 3%. Tiagabine (100 microg.) intrathecally in 7 rats reduced micturition pressure a mean of 34% +/- 10% and increased bladder capacity a mean of 30% +/- 9% and post-void residual volume a mean of 250% +/- 75%. However, voided volume was not changed. In vitro studies demonstrated that tiagabine attenuated bladder contractions induced by electrical field stimulation to a mean of 69% +/- 6% of controls at 100 microM. but did not affect contractions induced by carbachol. Release studies revealed that tiagabine inhibited electrical induced acetylcholine release to a mean of 82% +/- 5% of controls at 100 microM. CONCLUSIONS: The current results show that tiagabine has an inhibitory action on rat micturition. The site of action may be central and peripheral.
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