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- Bergendal, A, et al.
(författare)
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Extent of salmeterol-mediated reassertion of relaxation in guinea-pig trachea pretreated with aliphatic side chain structural analogues
- 1996
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Ingår i: British Journal of Pharmacology. - 1476-5381. ; 117:6, s. 1009-1015
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Tidskriftsartikel (refereegranskat)abstract
- 1. Salmeterol is a potent, selective and long acting beta 2-adrenoceptor agonist. In vitro, salmeterol exerts 'reassertion' relaxation of airways smooth muscle. Reassertion relaxation refers to the capacity of salmeterol to cause repeated functional antagonism of induced contraction when airway smooth muscle is intermittently exposed to, then washed free from, beta-adrenoceptor antagonists such as sotalol. The mechanism(s) underlying reassertion relaxation are unknown but may relate to high affinity binding of the long aliphatic side chain of salmeterol to an accessory site, distinct from the agonist recognition site, in or near the beta 2-adrenoceptor (exosite binding hypothesis). 2. In order to test the exosite hypothesis, three pure analogues of salmeterol, each exactly preserving the molecular structure of the aliphatic side chain but with zero or low efficacy at the beta 2-adrenoceptor were synthesized. The effect of pre-incubating guinea-pig tracheal smooth muscle with these analogues on salmeterol-induced reassertion relaxation was determined. 3. Computer Assisted Molecular Modelling of these molecules revealed that each of them exactly preserved the low energy linear conformation of the aliphatic side chain of salmeterol. Measurement of lipophilicity (octanol:water partition coefficient; log P) and direct partition into synthetic membranes (membrane partition coefficient; Kpmem) showed that all compounds had high affinity for lipids and membranes. In particular the biophysical properties of CGP 59162 (log P 1.89, Kpmem 16500) were very similar to salmeterol (log P 1.73, Kpmem 16800). 4. Two of the analogues, CGP 54103 and D 2543 (1 microM), which are structural mimics of the side chain of salmeterol, differing slightly in their length, did not prevent either the initial relaxation induced by salmeterol (0.1 microM) or the reassertion relaxation; however, it was not possible to determine whether either of these molecules occupied the beta 2-adrenoceptor. 5. The third analogue, CGP 59162, which has the substituents on the active saligenin head group of salmeterol in transposed positions, itself exerted a weak beta 2-adrenoceptor-mediated relaxation antagonized by ICI 118551 (beta 2-selective antagonist) but not CGP 20712 (beta 1-selective antagonist) and, at higher concentrations CGP 59162 caused reassertion relaxation suggesting that it may occupy and activate the beta 2-adrenoceptor in a manner analogous to salmeterol. 6. CGP 59162, at concentrations up to ten fold molar excess, did not prevent or reduce salmeterol-induced reassertion relaxation. 7. In conclusion these data are not consistent with the existence of a distinct 'exosite' recognising the aliphatic side chain of salmeterol mediating reassertion.
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- Bergendal, G., et al.
(författare)
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Callosal atrophy in multiple sclerosis is related to cognitive speed
- 2013
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 19:7, s. 969-969
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Tidskriftsartikel (refereegranskat)abstract
- Bergendal G, Martola J, Stawiarz L, Kristoffersen-Wiberg M, Fredrikson S, Almkvist O. Callosal atrophy in multiple sclerosis is related to cognitive speed. Acta Neurol Scand: 2013: 127: 281-289. (C) 2012 John Wiley & Sons A/S. Background Long-term changes regarding corpus callosum area (CCA) and information processing speed in cognitive and sensory-motor tasks have rarely been studied in multiple sclerosis (MS). Objective and methods Information processing speed in cognitive (Symbol Digit Modalities Test, SDMT), sensory (visual and auditory reaction time) and motor (finger-tapping speed, FT; right and left hand) tasks as well as auditory inter-hemispheric transfer (verbal dichotic listening, VDL) was related to CCA, measured by MRI at baseline and at follow-up after nine years in 22 patients with MS. Possible confounding by demographic (age, gender and education), clinical (symptom onset, duration, severity of disease) and relative brain volume (RBV) as well as T2 lesion load was taken into account. Results The smaller the CCA at baseline, the slower was SDMT performance at baseline. In a similar way, CCA at follow-up was associated with poor SDMT result at follow-up. Furthermore, the higher the annual rate of change in CCA, the poorer was performance in VDL on the left ear and the more pronounced was the right ear advantage. A positive relationship between performance in VDL right ear and annual rate of change in RBV was also seen. Sensory-motor tests were not significantly associated with CCA. T2 lesion load at baseline was associated with FT performance at baseline. Demographic, clinical and radiological (RBV and T2 lesion load) characteristics did not confound the significant relation between CCA and SDMT. Conclusions CCA unlike RBV and T2 lesion load was associated with SDMT, which indicated a marked cognitive rather than perceptual-motor component.
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- Bergendal, G., et al.
(författare)
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Selective decline in information processing in subgroups of multiple sclerosis : An 8-year longitudinal study
- 2007
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Ingår i: European Neurology. - : S. Karger AG. - 0014-3022 .- 1421-9913. ; 57:4, s. 193-202
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system (CNS) that causes white matter and cortical lesions over many years. The CNS is selectively affected by the disease with a great variety of symptoms between patients. In this study, we describe the impact on various aspects of cognition over an 8-year follow-up period in 31 consecutive MS patients subgrouped as relapsing remitting (RR) MS, secondary progressive (SP) MS, and primary progressive (PP) MS. Results showed a differential pattern of cognitive decline already at baseline in speed of information processing. During the follow-up, a pronounced decline occurred in speed of information processing, finger-motor speed, copying geometrical designs, episodic memory, and visuospatial short-term memory. A striking difference was observed between a marked decline in visual reaction time, whereas no significant change was seen in auditory reaction time. In contrast, there was no time-related decline in verbal abilities. However, an initial marked cognitive impairment predicted further cognitive decline over the 8-year follow-up. Information-processing tests were found to be an especially strong predictor of long-term cognitive decline. In addition, high EDSS score at followup was associated with decline in information processes. Results also showed that SP-MS patients deteriorated significantly more than the other two groups, particularly in visual compared to auditory information processing. To conclude, cognitive decline appeared particularly in SP-MS patients and in visual information processing.
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| 10. |
- Einarsson, U, et al.
(författare)
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Multiple sclerosis in Stockholm County. A pilot study exploring the feasibility of assessment of impairment, disability and handicap by home visits
- 2003
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Ingår i: Clinical rehabilitation. - : SAGE Publications. - 0269-2155 .- 1477-0873. ; 17:3, s. 294-303
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Tidskriftsartikel (refereegranskat)abstract
- Objective: A pilot study performed within Stockholm County to evaluate the feasibility of collecting data using a comprehensive evaluation package administered in the home environment to assess impairment, disability and handicap in order to explore the consequences of multiple sclerosis (MS). Design: Home visits to 26 purposefully selected MS patients with different levels of disability, in both ordinary and sheltered living. The comprehensive evaluation package included: biographical data, Mini-Mental State Examination, Free Recall and Recognition of 12 Random Words Test, Symbol Digit Modalities Test, Beck Depression Index, Lindmark Motor Capacity Assessment, time to walk 10 metres, Nine-hole Peg Test, Barthel ADL Index, Katz Extended ADL Index, Frenchay Activities Index, Sickness Impact Profile and frequency of falls and injurious falls. Results: This pilot study demonstrates that the proposed methods can be used to evaluate MS patients differing in levels of disability and forms of living. The data collection method, based on home visits, was well accepted by the patients, their spouses and salaried personal assistants and could be performed within 2–21/2 hours. Conclusions: The evaluation package used in this pilot study is suitable for use in population-based studies and it should provide comprehensive information on the impact and consequences of MS on patients, and should contribute to the identification of areas in which the provision of rehabilitation and health care services needs to be improved.
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