Author Of 1 Presentation
LB1211 - Histaminergic basis of fatigue in Multiple Sclerosis (ID 2069)
The histaminergic tuberomammillary system through its varied connections control the circadian rhythm and regulate wakefulness and sleep, satiety and hunger, memory and learning, as well as energy and tiredness. Blocking brain histamine receptors lead to tiredness and sleep. In this study we examined if raising brain histamine levels can improve fatigue in severely fatigued patients with multiple sclerosis.
To validate the concept that raising brain histamine will alleviate fatigue in severely fatigued patients with multiple sclerosis
A strategy was developed to raise brain histamine by loading patients with l-histidine, the precursor for histamine. Conversion systemically from l-histidine to histamine was blocked using histidine decarboxylase inhibitor, lodosyn, which has no access to the brain across the blood brain barrier.All subjects received a fixed dose lodosyn, 50 mg po bid. Three groups of l-histidine loading wereundertaken. Group-1 received 250 mg po bid, Group-2 500 mg po bid and group 3, 1 gm po bid. Pharmacokinetic (PK) and pharmacodynamic (PD) studies were conducted to measure blood and CSF l-histidine and histamine levels before and during treatment. Response to treatment was gauged using the visualanalogue fatigue scale (VAFS), Fatigue severity scale (FSS) and the modified fatigue impact scales (MFIS). To be considered a responder, patients had to improve in all three scales and show at least a 20% improvement from their mean screening/baseline MFIS scores.
A dose-based response to improvement of fatigue was observed anywhere from 30% to 88% in MFIS scores with the least responders in Group 1 and most in Group 3. Improvement was noted in all three domains of the MFIS; the physical, cognitive and psychosocial. Improvement in the cognitive domain was associated with subjects reporting improved attention, concentration and improvement of the“brain fog”. Responders reported an overall sense of well being while others reported no change.
This proof -of-concept study has identified a population of MS patients with fatigue that respond to treatment using elevation of brain histamine. This novel approach opens up a new avenue to identify drugs that raise brain histamine as a mechanism of treatment of fatigue in MS and possibly other disorders with fatigue where histamine may play a pivotal role in the pathogenesis of this common and severely disabling symptom. Additionally this treatment could also provide an approach to help cognitive impairment in multiple sclerosis since raising brain histamine can facilitate also the enhanced release of a number of neurotransmitters including acetylcholine, implicated in the pathogenesis of cognitive impairment in various disorders including multiple sclerosis.