Controlled trial of thyrotropin releasing hormone tartrate in ataxia of spinocerebellar degenerations

Sobue, I; Takayanagi, Tetsuya; Nakanishi, Takao; Tsubaki, Tadao; Uono, M; Kinoshita, Masao; Igata, Akihiro; Miyazaki, Motoji; Yoshida, Masaki; Ando, Kazuya; Maruyama, Shoichi; Mitsuma, Terunori; Nihei, Noriyuki; Sakuma, Atsushi; Kato, Kyoichi

doi:10.1016/0022-510x(83)90008-4

Cited by 87 publications

(38 citation statements)

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“…The use of BCAAs to buffer extracellular glutamate pools and as a treatment in patients with amyotrophic lateral sclerosis has been reported (8-1 1), however, we could find no such report on the effect of BCAAs on SCD. For evaluation, we adopted the SCDscore, established for clinical evaluations of the symptoms of SCDpatients based on the ataxia evaluating manual of TRH-Tin a multi-center, placebo-controlled double blind study (1). The International Cooperative Ataxia Rating Scale, which the Ataxia Neuropharmacology Committee of the World Federation of Neurology proposed for the pharmacological assessment of cerebellar ataxia, was not yet available at the commencement of this trial (12).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, little response was evoked from TRHtherapy, which has been reported to have a beneficial effect on SCDin many studies. This lack of response may be due in part to the fact that the TRHwas administered only for one week; as its recommended regimen is for a two-week period (1,3,4). While there was no significant difference between the placebo (control) and TRH or BCAAtreatments, the BCAAtherapy showed a significant improvement in SCDscores relative to baseline (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Many studies have been performed to design a treatment protocol for SCD (1)(2)(3), but few satisfactory therapies have been established. Thyrotropin-releasing hormone (TRH) has had a central role in SCDtreatments, and several studies of this agent have been conducted (1,3,4). However, its effectiveness varies with the type or severity of disease, and someinvestigators report that TRHhas no significant effect compared with a placebo (4).…”

Section: Introductionmentioning

confidence: 99%

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Branched-Chain Amino Acid Therapy for Spinocerebellar Degeneration: A Pilot Clinical Crossover Trial.

et al. 1999

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Object: The potential effects of branched-chain amino acids (BCAAs)on spinocerebellar degeneration (SCD) were explored in eleven patients. Methods: The patients received 200 ml of BCAA-rich solution, 2 mg of thyrotropin-releasing hormone (TRH; protirelin), or a placebo daily for 7 days each in a random order. An SCDscore was used to quantify the severity of symptoms. Patients: Eleven patients with SCD(7 male, 4 female; mean age 60±ll; mean disease duration 5.5 years) participated in this study. Results: The meanSCDscore of the eleven patients improved significantly by the BCAAtreatment compared with the baseline. The conditions of five of the eleven patients (45 %) were clearly improved by the BCAAtreatment. All of the responders manifested predominantly cerebellar symptoms, but no prominent parkinsonian symptoms. Two patients with marked rigidity and akinesia did not respond to the treatment. Conclusion: Weconcluded that BCAAsdo have a beneficial effect on functional improvement in patients with SCD, and that further large scale studies are needed. (Internal Medicine 38: 401-406, 1999)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Branched-Chain Amino Acid Therapy for Spinocerebellar Degeneration: A Pilot Clinical Crossover Trial.

et al. 1999

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“…TRH stimulates cholinergic and monoaminergic turnover, depolarizes spinal motoneurons, enhances CNS arousal, modulates locomotor activity, regulates respiration, and modulates pain perception and epileptic threshold (for review, see Jackson, 1982;Metcalf, 1982;Sharif, 1985;Griffiths and Bennett, 1987;Winokur et al, 1989). Furthermore, TRH has been shown to have beneficial effects in depression (Prange et al, 1972), brain and spinal injuries (Faden, 1986), spinocerebellar degeneration (Sobue et al, 1983), and motoneuron diseases (Engel et al, 1983). Therapeutic indications of TRH for these diseases are, however, still very limited partially because of the pharmacokinetic profile of TRH.…”

Section: Abstract: Thyrotropin-releasing Hormone; Narcolepsy; Cataplmentioning

confidence: 99%

Effects of Thyrotropin-Releasing Hormone and Its Analogs on Daytime Sleepiness and Cataplexy in Canine Narcolepsy

et al. 1997

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The therapeutic potential of thyrotropin-releasing hormone (TRH) and TRH analogs in narcolepsy, a sleep disorder characterized by abnormal rapid eye movement (REM) sleep and daytime sleepiness, was examined using the canine model. The effects of TRH and the biologically stable TRH analogs CG3703, CG3509, and TA0910 on daytime sleep and cataplexy, a symptom of abnormal REM sleep, were assessed using polysomnographic recordings and the food elicited cataplexy test (FECT), respectively. CG3703 (100 and 400 g/kg, i.v.) and TA0910 (100 and 400 g/kg, i.v.) significantly increased wakefulness and decreased sleep in narcoleptic canines, whereas TRH (400 and 1600 g/kg, i.v.) had no significant effect. TRH (25-1600 g/kg, i.v.) and all three TRH analogs, CG3703 (6.25-400 g/kg, i.v., and 0.25-16 mg/kg, p.o.), CG3509 (25-1600 g/kg, i.v.), and TA0910 (25-1600 g/kg, i.v.), significantly reduced cataplexy in canine narcolepsy. These compounds did not produce any significant side effects during behavioral assays, nor did they alter free T 3 and T 4 levels in serum even when used at doses that completely suppressed cataplexy. Although more work is needed to establish the mode of action of TRH analogs on alertness and REM sleep-related symptoms, our results suggest a possible therapeutic application for TRH analogs in human sleep disorders.

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“…In addition, both hypocretin and TRH receptors are G-protein coupled receptors for neuropeptides, and that the TRH receptor exhibits the second highest (25%) homology (with the Y2 neuropeptide Y receptor having the highest homology) to the hypocretin receptors (Sakurai et al 1998), suggesting that TRH may play an important role in the pathophysiology of narcolepsy through an unknown specific interaction with the hypocretin system. TRH has been involved in several clinical trials for various disorders such as depression, amyotrophic lateral sclerosis, and spinocerebellar degeneration, often with disappointing results (Engel et al 1983;Metcalf 1982;Prange et al 1972;Sobue et al 1983), possibly due to lack of a detailed evaluation of the therapeutic effects using validated animal models. The negative results of clinical trials using TRH could therefore be explained by insufficient dosing, inappropriate routes of drug administration, drug tolerance or by the fact that TRH itself has a short half-life and poor access to the CNS (see Metcalf 1982).…”

mentioning

confidence: 99%

Chronic Oral Administration of CG-3703, a Thyrotropin Releasing Hormone Analog, Increases Wake and Decreases Cataplexy in Canine Narcolepsy

Riehl

Honda

Kwan

et al. 2000

Neuropsychopharmacology

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The effects on cataplexy and daytime sleep of acute and chronic oral administration of CG-3703, a potent TRH analog were assessed in canine narcolepsy. CG-3703 was found to be orally active and to reduce cataplexy (0.25 to 16 mg/kg) and sleep (8 and 16 mg/kg) in a dose-dependent manner. Two-week oral administration of Human narcolepsy is a chronic life-long disorder characterized by excessive daytime somnolence (EDS), abnormal manifestations of rapid eye movement (REM) sleep (hypnagogic hallucinations and sleep paralysis), and cataplexy (Aldrich 1992;Guilleminault 1994;. Cataplexy is a sudden loss of muscle tone in response to emotionally-exciting stimuli. It is akin to the muscle atonia that occurs during physiological REM sleep, but it occurs inappropriately during wakefulness (Aldrich 1992;Guilleminault 1994;. The current treatments for narcolepsy require the use of central nervous system (CNS) stimulants for EDS and antidepressants for cataplexy and abnormal REM sleep (Guilleminault 1994;Mitler et al. 1990;Thorpy and Goswami 1990). These treatments, however, are often unsatisfactory due to incomplete therapeutic efficacy, the occurrence of various side effects, and the rapid development of drug tolerance (Guilleminault 1994;Mitler et al. 1990;Thorpy and Goswami 1990). It is therefore necessary to explore more efficacious compounds with different pharmacological profiles for possible use in narcolepsy treatment.Canine narcolepsy is a naturally-occurring animal model of the human disorder. Like humans, narcoleptic canines exhibit short sleep latency, fragmented sleep patterns, and cataplexy (Kaitin et al. 1986;Nishino et al. 1998c;Riehl et al. 1998). Narcolepsy in Doberman pinschers and Labrador retrievers is caused by mutations in the gene encoding a receptor ( Hcrtr-2 ) for a novel neuropeptide, the hypocretins (orex- Received July 27, 1999; revised November 10, 1999; accepted December 23, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 23 , NO . 1 CG-3703, a TRH Analog, in Narcoleptic Dogs 35 ins) (Lin et al. 1999). Human and canine narcolepsy share similar pharmacological characteristics (see for a review). This model is thus an invaluable resource for the study of the pathophysiology and treatment of narcolepsy. To this end, the canine model has been used in numerous pharmacological experiments to dissect the mode of action of various compounds on their effects on wakefulness and cataplexy, and to screen new compounds for use as possible treatments for narcolepsy (see for a review).Thyrotropin releasing hormone (TRH) is a tripeptidic hormone (L-pyroglutamyl-L-histidyl-L-prolineamide) originally extracted from the hypothalamus (Boler et al. 1969). It is now known to be distributed widely in the CNS, with receptors reported to exist in structures such as the pituitary, cortex, brainstem, thalamus, hippocampus, amygdala, and spinal cord (see Griffiths and Bennett 1987;Jackson 1982;Metcalf 1982;Sharif 1985;and Winokur et al. 1989 for reviews). Besides its role in stimulating the release of thyroid stimul...

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Controlled trial of thyrotropin releasing hormone tartrate in ataxia of spinocerebellar degenerations

Cited by 87 publications

References 9 publications

Branched-Chain Amino Acid Therapy for Spinocerebellar Degeneration: A Pilot Clinical Crossover Trial.

Branched-Chain Amino Acid Therapy for Spinocerebellar Degeneration: A Pilot Clinical Crossover Trial.

Effects of Thyrotropin-Releasing Hormone and Its Analogs on Daytime Sleepiness and Cataplexy in Canine Narcolepsy

Chronic Oral Administration of CG-3703, a Thyrotropin Releasing Hormone Analog, Increases Wake and Decreases Cataplexy in Canine Narcolepsy

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