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- Andersson, Karl-Erik, et al.
(author)
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Pharmacologic perspective on the physiology of the lower urinary tract
- 2002
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In: Urology. - : Elsevier. - 0090-4295 .- 1527-9995. ; 60:5 Suppl 1, s. 13-20
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Journal article (peer-reviewed)abstract
- Myogenic activity, distention of the detrusor, and signals from the urothelium may initiate voiding. In the bladder, afferent nerves have been identified not only in the detrusor, but also suburothelially, where they form a plexus that lies immediately beneath the epithelial lining. Extracellular adenosine triphosphate (ATP) has been found to mediate excitation of small-diameter sensory neurons via P2X3 receptors, and it has been shown that bladder distention causes release of ATP from the urothelium. In turn, ATP can activate P2X3 receptors on suburothelial afferent nerve terminals to evoke a neural discharge. However, most probably, not only ATP but also a cascade of inhibitory and stimulatory transmitters and mediators are involved in the transduction mechanisms underlying the activation of afferent fibers during bladder filling. These mechanisms may be targets for future drugs. The central nervous control of micturition involves many transmitter systems, which may be suitable targets for pharmacologic intervention. gamma-Aminobutyric acid, dopamine, enkephalin, serotonin, and noradrenaline receptors and mechanisms are known to influence micturition, and potentially, drugs that affect these systems could be developed for clinical use. However, a selective action on the lower urinary tract may be difficult to obtain. Most drugs currently used for treatment of detrusor overactivity have a peripheral site of action, mainly the efferent (cholinergic) neurotransmission and/or the detrusor muscle itself. In the normal bladder, muscarinic receptor stimulation produces the main part of detrusor contraction, but evidence is accumulating that in disease states, such as neurogenic bladders, outflow obstruction, idiopathic detrusor instability, and interstitial cystitis, as well as in the aging bladder, a noncholinergic activation via purinergic receptors may occur. If this component of activation is responsible not only for part of the bladder contractions, but also for the symptoms of the overactive bladder, it should be considered an important target for therapeutic interventions.
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| 5. |
- Modiri, Ali-Reza, et al.
(author)
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Effect of muscarinic antagonists on micturition pressure measured by cystometry in normal, conscious rats
- 2002
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In: Urology. - 0090-4295 .- 1527-9995. ; 59:6, s. 963-968
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To establish an in vivo model to screen new muscarinic antagonists for the treatment of overactive urinary bladder and to calculate the respective ID(50) values.METHODS: The conscious rat cystometry model was modified to determine a complete dose-response curve in each animal. Spontaneous micturition was induced by infusion of room-temperature saline into rat bladders at a constant rate of 12 mL/hr. Cumulative doses of muscarinic antagonists administered in the femoral vein caused dose-dependent inhibition of the urinary bladder contraction measured as the micturition pressure. In addition, the in vitro pK(B) values for atropine, PNU-200577 (DD01), tolterodine, oxybutynin, and terodiline were determined in carbachol-contracted rat bladder strips.RESULTS: The rank order of the in vivo ID(50) values were atropine (14 +/- 4 nmol/kg), PNU-200577 (22 +/- 12 nmol/kg), tolterodine (94 +/- 20 nmol/kg), oxybutynin (175 +/- 89 nmol/kg), darifenacin (236 +/- 144 nmol/kg), desethyloxybutynin (313 +/- 209 nmol/kg), propiverine (4561 +/- 2079 nmol/kg), and terodiline (18,339 +/- 5348 nmol/kg). Tolterodine and PNU-200577 caused a parallel shift of the in vitro concentration-response curve to the right and did not alter the maximal contraction. The ID(50) values correlated significantly with the in vitro rat pK(B) and human bladder pA(2) values.CONCLUSIONS: The present results suggest that the rat cystometry model can be used in in vivo screening for new muscarinic antagonists.
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| 6. |
- Sandblom, Gabriel, et al.
(author)
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Long-term survival in a swedish population-based cohort of men with prostate cancer
- 2000
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In: Urology. - 0090-4295 .- 1527-9995. ; 56:3, s. 442-447
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Journal article (peer-reviewed)abstract
- Objectives. To study the long-term survival of patients with prostate cancer, determine the risk factors for prostate cancer death, and investigate the outcome of initially untreated localized prostate cancer and incidentally detected tumors.Methods. The survival of 813 patients in a population-based cohort of patients with prostate cancer in Linköping, Sweden, diagnosed from 1974 to 1986, was analyzed.Results. At 10, 15, and 20 years after diagnosis, the prostate cancer-specific survival rate of men with localized, initially untreated, prostate cancer was 85.0% (95% confidence interval [CI], 79.0% to 91.0%), 80.0% (95% CI, 72.5% to 87.5%), and 62.6% (95% CI, 43.0% to 82.2%). Age 70 years or older, advanced stage, and poor differentiation were risk factors associated with an increased risk of prostate cancer death. At 10 years, the prostate cancer-specific survival rate among men with localized tumors treated by expectancy was 90% (95% CI, 84% to 97%) for grade 1 tumors, 74% (95% CI, 60% to 89%) for grade 2 tumors, and 59% (95% CI, 29% to 90%) for grade 3 tumors. For patients with incidentally detected tumors, the grade of malignancy was a more important risk factor than tumor volume.Conclusions. Patients with localized tumors have a favorable prognosis, even without initial treatment. However, when deciding on therapy, the grade of malignancy should be taken into account, as it has a great influence on survival. We did not see a tendency toward increased mortality when the patients were followed up for longer than 10 years after diagnosis.
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- Andersson, Karl-Erik
(author)
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New pharmacologic targets for the treatment of the overactive bladder: an update.
- 2004
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In: Urology. - : Elsevier BV. - 1527-9995 .- 0090-4295. ; 63:3 Suppl 1, s. 32-41
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Journal article (peer-reviewed)abstract
- Although currently available antimuscarinic agents are the standard of care for overactive bladder (OAB), they are limited by certain side effects, particularly dry mouth and constipation. Research aimed at discovering new therapies for OAB has resulted in the identification of some promising drugs. Investigations of pharmacologic targets in the central nervous system (CNS) have yielded encouraging results with several agents, including tramadol and gabapentin. Further investigation may show that drugs acting at serotonergic and noradrenergic CNS sites are clinically useful as therapies for OAB. Some peripherally acting drugs, such as resiniferatoxin and botulinum toxin, have already been proved to be of clinical value. However, development of other agents that block afferent or efferent nerve impulses in the bladder through activity at vanilloid, purinergic, or opioid-like receptor sites may result in clinically useful drugs.
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| 9. |
- Andersson, Karl-Erik
(author)
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Storage and voiding symptoms: pathophysiologic aspects.
- 2003
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In: Urology. - : Elsevier BV. - 1527-9995 .- 0090-4295. ; 62:5 Suppl 2, s. 3-10
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Journal article (peer-reviewed)abstract
- Lower urinary tract symptoms (LUTS) can be categorized as storage, voiding, and postmicturition symptoms. Although often associated with benign prostatic hyperplasia (BPH), they may also occur in women. This observation, the beneficial effects of a-adrenoceptor (AR) antagonists in men with BPH and LUTS, and the frail correlation between LUTS, and prostatic enlargement and/or outflow obstruction have focused interest on the role of extraprostatic alpha-ARs in the pathogenesis of LUTS. It has been suggested that an upregulation of contraction-mediating alpha-ARs and a downregulation of relaxation-mediating beta-ARs can contribute to LUTS generation. However, recent investigations on human bladder tissue could not confirm such a change. Antimuscarinic agents are effective for treatment of the overactive bladder, which is characterized by urge, frequency, urge incontinence, and nocturia (ie, LUTS). This suggests that muscarinic receptors are involved in the pathogenesis of LUTS, and there is recent evidence implicating purinergic receptors. Structural changes in the bladder, such as smooth muscle hypertrophy and connective tissue infiltration, are associated with detrusor overactivity in about 50% to 66% of patients with BPH. However, it is unclear whether this is caused by bladder outlet obstruction because the symptoms may remain in up to 33% of the patients after surgical removal of the obstruction. When outflow obstruction is reversed in rats, there is a subset (20%) that continues to have overactive voiding, despite a reversal of the bladder hypertrophy, suggesting that changes within the central nervous system may be a contributing factor. LUTS can be caused by many, often overlapping, pathophysiologic mechanisms, which may contribute to individual variation in response to treatment.
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