| 1. |
- Bødker, Anders, et al.
(författare)
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Estrogen receptors in the human male bladder, prostatic urethra, and prostate. An immunohistochemical and biochemical study
- 1995
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Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 29:2, s. 161-165
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Tidskriftsartikel (refereegranskat)abstract
- The distribution and quantity of estrogen receptors (ERs) in the human male bladder, prostatic urethra and the prostate were studied in eight males with recurrent papillomas of the bladder or monosymptomatic hematuria (median age 61 years), 14 men undergoing transurethral resection due to benign prostatic hyperplasia (median age 70 years), and nine men undergoing cystectomy due to malignant tumour of the bladder (median age 70 years). In the first group of patients, biopsies for immunohistochemical examination were obtained from the bladder vault, bottom, both side-walls, the trigone area, and the mid-portion of the prostatic urethra, and in the second group from three locations of the prostatic urethra (bladder neck, mid-portion and veramontanum). In the third group, tissue specimens were taken from the vault of the bladder, prostatic urethra, and the prostate, for immunohistochemical as well as biochemical analysis. In the first group, ERs were found in three out of eight specimens of the prostatic urethra, and in one of these, ERs were confined to periurethral glands. ERs could not be demonstrated in any of the bladder-biopsies. In the second group, ERs were not found in the bladder neck, but were seen in four preparations from the veramontanum and in two from the midportion of the urethra. ERs were located in the urothelium and periurethral glands. In the third group, ERs were seen immunohistochemically in the prostatic urethra (two cases) and the prostatic stromal tissue (two cases). ERs could be demonstrated in the bladder neither by immunohistochemistry nor biochemically.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 2. |
- Hedlund, H., et al.
(författare)
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Pharmacotherapy in erectile dysfunction agents for self-injection programs and alternative application models
- 1996
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Ingår i: Scandinavian Journal of Urology and Nephrology, Supplementum. - 0300-8886 .- 1651-2537. ; 179, s. 129-38
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Forskningsöversikt (refereegranskat)abstract
- Previously, men with erectile dysfunction (ED) were frequently treated with penile prosthesis implants or considered to have psychogenic impotence. Since the reports by Virag and Brindley in 1932 and 1983, pharmacotherapy, by self-injection programs has become a new therapeutic concept for impotent men. In clinical practice, this application model has been generally accepted as the "golden standard" in the treatment of ED. Papaverine was first used as monotherapy, but because of side-effects such as prolonged erection, priapism, and fibrosis of the corpus cavernosum, single use of the drug was abandoned. Instead, papaverine was introduced in mixtures, e.g. together with alpha adrenoceptor-blockers as phentolamine, and/or prostaglandin E1 (PGE1) in these "cocktails", the dose of papaverine is reduced to 10-15 mg compared to the high doses (80-120 mg) that were used initially. By having two or more drugs in the mixture, a facilitating cascade effect as probably obtained. PGE1 is the only drug that has been approved by the FDA and is today registered in more than 50 countries. Other combination therapies such as vasoactive intestinal polypeptide+ phentolamine, or calcitonin gene-related peptide+ PGE1, have been suggested as suitable alternatives for intracavernosal injection. Transdermal and intraurethral application models may be considered in selected patients. Recently, oral administration of a phosphodiesterase inhibitor (UK-92.480) was reported to improve penile erection in patients with psychogenic impotence. Further clinical results from controlled trials will probably explain if this new oral drug will compete with PGE1 or other agents in self-injection programs.
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| 3. |
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| 4. |
- Hedlund, Petter, et al.
(författare)
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Effects of nicorandil on human isolated corpus cavernosum and cavernous artery
- 1994
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Ingår i: Journal of Urology. - : Elsevier. - 0022-5347 .- 1527-3792. ; 151:4, s. 1107-1113
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Tidskriftsartikel (refereegranskat)abstract
- Nitric oxide (NO) released from nonadrenergic-noncholinergic (NANC) nerves seems to be a principal mediator of the relaxation of penile erectile tissue necessary for erection, and drugs acting by release of NO have been shown to produce erection when injected intracorporeally into impotent patients. By producing hyperpolarization, K+ channel openers are effective in relaxing isolated penile erectile tissue from rabbit and man, and can produce tumescence and erection when injected intracorporeally into animals. Nicorandil is classified as a K+ channel opener, but it also acts as a donor of NO. In the present study, the effects of nicorandil on isolated preparations from human corpus cavernosum (CC) and deep cavernous artery (Acc) were compared with those of cromakalim (K+ channel opener) and SIN-1 (NO donor). Nicorandil produced a concentration-dependent relaxation of CC and Acc preparations. The relaxations obtained at the highest nicorandil concentration used (10(-4) M.) were 75 +/- 3% and 66 +/- 4% in CC preparations contracted by noradrenaline and endothelin-1, respectively. The corresponding effects in Acc preparations were 70 +/- 14% and 73 +/- 5%. Glibenclamide (blocking ATP-dependent K+ channels) significantly reduced the nicorandil-induced relaxation in CC, but not in Acc. Methylene blue (believed to block soluble guanylate cyclase) reduced nicorandil's relaxant effect in CC, although statistical significance was not obtained. NG-nitro-L-arginine 10(-4) M. (NO synthase inhibitor) did not significantly influence the effect of nicorandil on precontracted preparations in either tissue. In CC preparations contracted by electrical field stimulation, nicorandil and cromakalim concentration dependently inhibited the responses. This effect was significantly counteracted by glibenclamide. It is concluded that nicorandil is effective in relaxing human CC chiefly by its K+ channel opening action, and to some extent by its ability to release NO. For nicorandil's relaxing effect on Acc, ATP dependent K+ channels seem to be of limited importance. If effective in impotent patients, the drug may represent a new, interesting approach to the treatment of erectile dysfunction.
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| 5. |
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| 6. |
- Hedlund, Petter, et al.
(författare)
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Pituitary adenylate cyclase-activating polypeptide, helospectin, and vasoactive intestinal polypeptide in human corpus cavernosum
- 1995
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Ingår i: British Journal of Pharmacology. - 0007-1188 .- 1476-5381. ; 116:4, s. 2258-2266
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Tidskriftsartikel (refereegranskat)abstract
- 1. The distribution and effects of pituitary adenylate cyclase-activating polypeptide (PACAP-27 and -38), helospectin (Hel-1 and Hel-2), and vasoactive intestinal polypeptide (VIP), were investigated in isolated preparations of human corpus cavernosum (CC). 2. Immunohistochemistry revealed coinciding profiles of nerve structures that showed immunoreactivities for VIP and PACAP, and VIP and Hel. Confocal microscopy showed the co-existence of VIP- and PACAP-immunoreactivities, and VIP- and Hel-immunoreactivities in most (90%) varicose nerve structures. 3. As determined by radioimmunoassay, the amounts of VIP, PACAP-27, and PACAP-38 in the preparations were 61.7 +/- 11.6, 0.1 +/- 0.05, and 3.7 +/- 0.5 pmol g-1 wet weight of tissue (pmol g-1 wet wt.), respectively. In tissue from patients with diabetes, the content of VIP was lower (13.7 +/- 0.5 pmol g-1 wet wt.), whereas that of PACAP (-27 and -38) was unchanged. 4. Cyclic nucleotide levels were determined in preparations exposed to PACAP-27, PACAP-38, Hel-1, Hel-2, and VIP. All the peptides, but Hel-2, significantly increased the concentrations of cyclic AMP, whereas the levels of cyclic GMP were unchanged. 5. The peptides concentration-dependently relaxed noradrenaline-contracted preparations. The order of potency was VIP > PACAP 27 > Hel-1 > Hel-2 > PACAP-38. 6. Hel-1, VIP and PACAP-27 effectively counteracted electrically induced contractions. At 10(-6) M, the highest peptide concentration used, the inhibitory effects obtained reached 96 +/- 3%, 87 +/- 6%, and 80 +/- 3%, respectively. 7. The results suggest that PACAP and Hel-1 are co-localized with VIP in nerve structures within the human cavernous tissue, and that the peptides are effective relaxants of CC preparations in vitro. The role of the investigated peptides for penile erection remains to be established.
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| 7. |
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| 8. |
- Abrate, Alberto, et al.
(författare)
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Mesenchymal stem cells expressing therapeutic genes induce autochthonous prostate tumour regression
- 2014
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Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 50:14, s. 2478-2488
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Tidskriftsartikel (refereegranskat)abstract
- Mesenchymal stem cells (MSC) as vehicles of therapeutic genes represent a unique tool to activate drugs within a neoplastic mass due to their property to home and engraft into tumours. In particular, MSC expressing the cytosine deaminase:: uracil phosphoribosyltransferase (CD-MSC) have been previously demonstrated to inhibit growth of subcutaneous prostate cancer xenografts thanks to their ability to convert the non-toxic 5-fluorocytosine into the antineoplastic 5-fluorouracil. Since both the immune system and the tumour microenvironment play a crucial role in directing cancer progression, in order to advance towards clinical applications, we tested the therapeutic potential of this approach on animal models that develop autochthonous prostate cancer and preserve an intact immune system. As cell vectors, we employed adipose-tissue and bone-marrow MSC. CD-MSC toxicity on murine prostate cancer cells and tumour tropism were verified in vitro and ex-vivo before starting the preclinical studies. Magnetic Resonance Imaging was utilised to follow orthotopic tumour progression. We demonstrated that intravenous injections of CD-MSC cells, followed by intraperitoneal administration of 5-fluorocytosine, caused tumour regression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which develops aggressive and spontaneous prostate cancer. These results add new insights to the therapeutic potential of specifically engineered MSC in prostate cancer disease.
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| 9. |
- Aizawa, Naoki, et al.
(författare)
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Inhibition of Peripheral FAAH Depresses Activities of Bladder Mechanosensitive Nerve Fibers of the Rat
- 2014
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Ingår i: Journal of Urology. - : Elsevier. - 0022-5347 .- 1527-3792. ; 192:3, s. 956-963
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: FAAH degrades endocannabinoids and fatty acid amides. FAAH inhibition reduces micturition frequency and counteracts bladder overactivity in rats. We studied the effects of the peripherally active selective FAAH inhibitor URB937, and the CB1 and CB2 receptor antagonists rimonabant and SR144528, respectively, on single unit afferent activity of primary bladder afferents in rats. Materials and Methods: Female Sprague Dawley (R) rats were anesthetized. Single unit afferent activity of A delta or C-fibers from the L6 dorsal roots was recorded during bladder filling before and after URB937 administration with or without rimonabant or SR144528. Drugs (1 mg/kg) were given intravenously. FAAH, CB1 and CB2 expression, and expression of the sensory marker CGRP in the L6 dorsal root ganglion were compared by immunofluorescence. Results: A total of 102 single afferent fibers (48 A delta and 54 C-fibers) were isolated from 57 rats. URB937 decreased single unit afferent activity of C-fibers to a mean +/- SEM of 78% +/- 9% and of A delta-fibers to a mean of 67% +/- 7% while increasing bladder compliance to a mean of 116% +/- 3%. The effects of URB937 on single unit afferent activity and bladder compliance were counteracted by rimonabant or SR144528. Rimonabant increased single unit afferent activity of each fiber type but SR144528 affected only A delta-fiber activity. CGRP positive L6 dorsal root ganglion neurons showed strong FAAH, CB1 and CB2 staining. Conclusions: To our knowledge we report for the first time that inhibiting peripheral FAAH depresses the Ad and C-fiber activity of primary bladder afferents via CB1 and CB2 receptors. CB antagonists alone exerted facilitatory effects on single unit afferent activity during bladder filling in rats. The endocannabinoid system may be involved in physiological control of micturition as regulators of afferent signals.
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| 10. |
- Aizawa, Naoki, et al.
(författare)
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URB937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E-2-induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibres in rats
- 2016
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Ingår i: BJU International. - : WILEY-BLACKWELL. - 1464-4096 .- 1464-410X. ; 117:5, s. 821-828
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Tidskriftsartikel (refereegranskat)abstract
- Objective To determine if inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) can counteract the changes in urodynamic variables and bladder afferent activities induced by intravesical prostaglandin E-2 (PGE(2)) instillation in rats. Materials and methods In female Sprague-Dawley rats we studied the effects of URB937, a peripherally restricted FAAH inhibitor, on single-unit afferent activity (SAA) during PGE(2)-induced bladder overactivity (BO). SAA measurements were made in urethane-anaesthetised rats and Ad-and C-fibres were identified by electrical stimulation of the pelvic nerve and by bladder distention. Cystometry (CMG) in conscious animals and during SAA measurements was performed during intravesical instillation of PGE(2) (50 or 100 mu M) after intravenous administration of URB937 (0.1 and 1 mg/kg) or vehicle. In separate experiments, the comparative expressions of FAAH and cannabinoid receptors, CB1 and CB2, in microsurgically removed L6 dorsal root ganglion (DRG) were studied by immunofluorescence. Results During CMG, 1 mg/kg URB937, but not vehicle or 0.1 mg/kg URB937, counteracted the PGE(2)-induced changes in urodynamic variables. PGE(2) increased the SAAs of C-fibres, but not Ad-fibres. URB937 (1 mg/kg) depressed Ad-fibre SAA and abolished the facilitated C-fibre SAA induced by PGE(2). The DRG nerve cells showed strong staining for FAAH, CB1 and CB2, with a mean (SEM) of 77 (2)% and 87 (3)% of FAAH-positive nerve cell bodies co-expressing CB1 or CB2 immunofluorescence, respectively. Conclusion The present results show that URB937, a peripherally restricted FAAH inhibitor, reduces BO and C-fibre hyperactivity in the rat bladder provoked by PGE(2), suggesting an important role of the peripheral endocannabinoid system in BO and hypersensitivity.
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