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  • Fertility and education  (2)
  • 5-HT  (1)
  • Animal models  (1)
  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Inflammation research 45 (1996), S. 531-540 
    ISSN: 1420-908X
    Keywords: Antiinflammatory ; Analgesic ; Antipyretic ; pKa ; Octanol-water partition coefficient ; NSAIDs ; Animal models ; Carrageenin ED50
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective and Design: Relevance of the preclinical pharmacodynamic, toxicity and pharmacokinetic parameters predicting the clinical potency of nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated. Material: Data for oral potencies of 24 NSAIDs in rats were collected from the literature and from New Drug Applications with respect to the following parameters: antiinflammatory, analgesic, antipyretic, acute ulcerogenic activities, acute toxicity, in vitro inhibition of prostaglandin synthesis, acid dissociation constant (pKa), octanolwater partition coefficient and elimination half-life. Treatment: Data for most of the in vivo parameters in rats were collected following single dose administration with the exception of adjuvant arthritis. Single and daily clinical doses were considered. All of these NSAIDs have been approved for marketing although not all have been sold in the USA. Methods: The preclinical data were compared to human dose (unit or daily doses) using single and multiple stepwise regression analyses. Results: Analyses suggest that NSAIDs are effective in all models of preclinical tests for fever, pain and inflammation, however, carrageenin-induced rat paw edema model is clearly the best predictor of human dose. Rank order of preclinical models for predicting human dose is carrageenin 〉yeast induced fever〉pressure induced pain=adjuvant arthritis in rats. The analysis suggested that the pain and adjuvant arthritis models in rats may also involve a prostaglandin independent mechanism. Of the two physicochemical factors tested, pKa contributed best to the carrageenin model towards predicting the clinical potency of NSAIDs. Mathematical relationships between human dose, carrageenin ED50 and pKa were established that may assist in the future clinical development of NSAIDs. Conclusions: Carrageenin-induced paw edema model in rats is the most robust predictor of the clinical potency of NSAIDs. Acid dissociation constant (pKa) appears to be a secondary contributor to the potency of NSAIDs. The relevance of the data analyses for developing cyclooxygenase-2 (COX-2) selective NSAIDs is discussed.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 111 (1996), S. 57-67 
    ISSN: 1432-1106
    Keywords: 5-HT ; Locomotion ; Motor control ; Pattern generation ; Spinal cord ; Mudpuppy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The aims of the present study were to: (1) study the role of serotonin (5-HT) in modulating the central pattern generator (CPG) underlying locomotion in the mudpuppy (Necturus maculatus); (2) investigate whether there is an intrinsic spinal serotonergic system. These aims were achieved by the use of pharmacological and immunocytochemical methods. To study modulation of the locomotor pattern and rhythm, we applied 5-HT, its uptake blocker zimelidine, and a variety of 5-HT receptor agonists and antagonists to an in vitro brainstemspinal cord preparation isolated from the mudpuppy. The preparation consisted of the first five segments of the spinal cord and the right forelimb attached by the brachial plexus. The spinal CPG for locomotion was activated chemically by adding NMDA to the superfusing solution. During locomotion, bipolar electromyographic (EMG) recordings were made unilaterally from flexor and extensor ulnae muscles. 5-HT on its own did not induce locomotion, but it did have a profound modulatory effect on NMDA-induced locomotion. 5-HT produced a dose-dependent increase in the overall cycle duration and enhanced the EMG burst duration. Use of zimelidine indicated that there is an endogenous release of 5-HT which modulated the locomotor rhythm. The endogenous release was antagonized by 5-HT1/5-HT2 receptor antagonist methiothepin. Immunocytochemical analysis, in which the entire spinal cord of the mudpuppy was used, revealed that there were more than one type of spinal serotonergic neuron. They were differentiated according to the cell diameter, shape, and arborization pattern of their processes. These neurons were located within the central gray matter ventrolateral to the central canal. Our results suggest that 5-HT plays an important role in modulating the locomotor CPG in the mudpuppy, by acting through a well-developed spinal serotonergic system. This is in contrast to what has been reported in higher vertebrates, where serotonergic innervation is derived from supraspinal structures.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-1076
    Keywords: Key words Bladder exstrophy ; Interpersonal relations ; Sexual ; behaviour ; Fertility and education
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract After primary bladder closure or urinary diversion, other factors apart from the reconstruction itself gain importance for individuals with the exstrophy-epispadias complex: social integration and, after reaching puberty, sexuality and fertility. Between 1968 and July 1994 115 patients with bladder exstrophy or incontinent epispadias underwent surgery at our institution. A total of 104 patients could be followed, 2 of whom died in the meantime. Of the remaining 102 patients 48 attend school, 4 are in college, 40 have completed or are currently undergoing vocational training, 3 are unemployed, 1 lives in a therapeutic centre and 6 are younger than 6 years of age. A total of 95% of the patients with continent urinary diversion are continent day and night, whereas only three of five patients with a sling plasty (incontinent epispadias) or with primary bladder closure followed by a Young-Dees procedure are continent. None of the patients showed deterioration of renal function. In 25 females the external genitalia were reconstructed. Fixation of the uterus was done in 13 to correct or prevent uterine prolapse. Of the 17 women older than 18 years of age with genital reconstruction, 16 are satisfied with the cosmetic result. All adults engage in sexual intercourse. Five women have delivered seven children by Caesarean section. Of the 35 male adults 32 underwent reconstruction of the external genitalia and 34 males achieve erection. One developed necrosis of the penis early in life following primary bladder closure performed at an outside hospital. Penile deviation was present in 11 of the 32 patients with genital reconstruction, which is distressing in only 2. Thirty patients are satisfied with the cosmetic result. After genital reconstruction 9 males developed epididymitis, necessitating two orchiectomies and three vasectomies. No patient with reconstruction of the external genitalia can ejaculate normally or has fathered children, whereas ejaculation was normal in the three men who did not undergo genital reconstruction and in two patients prior to post-pubertal reconstruction. Furthermore, two of these three men have fathered four children. Conclusion Education, occupation and social development of patients with urinary diversion are uneventful. The cosmetic results achieved by genital reconstruction are satisfactory. In female patients, antefixation of the uterus should be performed before or together with an introitusplasty to prevent uterine prolapse. In male patients, however, surgery is performed at the expense of fertility. Detailed discussions with the patients and their parents should include not only the question of primary bladder closure versus urinary diversion, but also the pros and cons of correction of the external and – in females – the internal genitalia.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1076
    Keywords: Bladder exstrophy ; Interpersonal relations ; Sexual behaviour ; Fertility and education
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract After primary bladder closure or urinary diversion, other factors apart from the reconstruction itself gain importance for individuals with the exstrophy-epispadias complex: social integration and, after reaching puberty, sexuality and fertility. Between 1968 and July 1994 115 patients with bladder exstrophy or incontinent epispadias underwent surgery at our institution. A total of 104 patients could be followed, 2 of whom died in the meantime. Of the remaining 102 patients 48 attend school, 4 are in college, 40 have completed or are currently undergoing vocational training, 3 are unemployed, 1 lives in a therapeutic centre and 6 are younger than 6 years of age. A total of 95% of the patients with continent urinary diversion are continent day and night, whereas only three of five patients with a sling plasty (incontinent epispadias) or with primary bladder closure followed by a Young-Dees procedure are continent. None of the patients showed deterioration of renal function. In 25 females the external genitalia were reconstructed. Fixation of the uterus was done in 13 to correct or prevent uterine prolapse. Of the 17 women older than 18 years of age with genital reconstruction, 16 are satisfied with the cosmetic result. All adults engage in sexual intercourse. Five women have delivered seven children by Caesarean section. Of the 35 male adults 32 underwent reconstruction of the external genitalia and 34 males achieve erection. One developed necrosis of the penis early in life following primary bladder closure performed at an outside hospital. Penile deviation was present in 11 of the 32 patients with genital reconstruction, which is distressing in only 2. Thirty patients are satisfied with the cosmetic result. After genital reconstruction 9 males developed epididymitis, necessitating two orchiectomies and three vasectomies. No patient with reconstruction of the external genitalia can ejaculate normally or has fathered children, whereas ejaculation was normal in the three men who did not undergo genital reconstruction and in two patients prior to post-pubertal reconstruction. Furthermore, two of these three men have fathered four children.
    Type of Medium: Electronic Resource
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