Controlled acute trial of a thyrotrophin releasing hormone analogue (RX77368) in motor neuron disease (original) (raw)
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Subacute administration of a TRH analogue (RX77368) in motorneuron disease: an open study
Journal of Neurology, Neurosurgery & Psychiatry, 1988
Sixteen patients with motor neuron disease received RX77368, a TRH analogue, IV, repeatedly over 1-12 weeks (median 2 weeks). Slight to moderate improvement in bulbar function, particularly speech, was reproduced or persisted with repeated infusions in 8 of 12 responders over a median of 18 days (range 14-90) during the period of study. Cramps (5/9) and spasticity (5/8) improved for a median of 14 days (range 7-35) and 7 days (range 2-14) respectively. The highest benefit/side effect ratio was seen with 0-2 mg/kg (0-15 mg/kg in those with severe bulbar palsy) every 3-4 days. Long term studies with this analogue in MND are indicated.
A Summary of the Current Position of TRH in ALS Therapy
Annals of the New York Academy of Sciences, 1989
Thyrotropin-releasing hormone (TRH), pyroglutamyl-histidyl-prolineamide, is a tripeptide present in the central nervous system with profound neurophysiological and presumed ergotropic and trophic effects. The pharmacological response to TRH is extremely state dependent.laZo In addition, this tripeptide has autonomic and sudomotor effects including tachycardia, tachypnea, diaphoresis, increased systolic and diastolic blood pressure, and shivering.21.22 These side effects seriously interfere with evaluating whether TRH may have a short-term physiologic or long-term trophic effect on motor neuron function in patients with amyotrophic lateral sclerosis (ALS). Clinical investigations employing different doses, routes of administration, and chemical forms of TRH have been reported since 1983 (TABLES 1-4). Some investigations have suggested definite clinical benefit.7r2s27 Other investigations have not confirmed that there was a consistent clinical benefit.2G3t All clinical
Use of TRH Analogues in Motorneurone Disease
Annals of the New York Academy of Sciences, 1989
Sporadic motorneurone disease (MND) or amyotrophic lateral sclerosis (ALS) was described by Charcot in 1874.' It is a serious progressive human disease with a 75% mortality within 5 years of clinical onset. Its incidence is about 1-1.5 per 100,OOO~ a figure similar to that of multiple sclerosis, but its prevalence is much less because in multiple sclerosis prolonged survival is the rule. The condition is
Neuropharmacology, 2015
JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective therapeutic candidate offering a multifaceted approach to treating neurodegeneration and other CNS conditions. The purpose of these studies was to determine the ability of JAK4D to bind to TRH receptors in human brain and to evaluate its neuropharmacological effects in neurodegenerative animal models. Additionally, JAK4D brain permeation was examined in mouse, and initial toxicology was assessed in vivo and in vitro. We report that JAK4D bound selectively with nanomolar affinity to native TRH receptors in human hippocampal tissue and showed for the first time that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus revealing a new TRH receptor subtype which represents a promising neurotherapeutic target in human brain. Systemic administration of JAK4D elicited statistically significant and clinically-relevant neuroprotective effects in three established...
The American journal of physiology, 1992
We sought to characterize the excitatory effect of thyrotropin-releasing hormone (TRH) in dorsal motor nucleus of the vagus (DMV) motoneurons by using the patch-clamp technique in rat brain stem slices. In our initial studies we used the cell-attached recording configuration using concentrations of TRH from 1 to 30 microM. Exposure of DMV motoneurons to TRH resulted in a concentration-related increase in spontaneously occurring action potential firing rate. This was observed in 63 of 85 DMV neurons (75%) tested and was unrelated to their location rostral or caudal to the obex. Invariably, desensitization occurred to the excitatory effect of TRH. Subsequent experiments using whole cell recordings in the current-clamp mode confirmed that TRH excites DMV neurons located both rostral and caudal to the obex. In the current-clamp configuration, TRH produced depolarization; i.e., 30 microM TRH elicited a depolarization of 8.7 +/- 3.2 mV (P < 0.05, n = 7). Studies using whole cell curren...
Journal of Neurology, Neurosurgery & Psychiatry, 1995
The continuous response variable controlled trial design is developed as a model for the efficient screening of candidate treatments in motor neuron disease. A TRH analogue (RX77368) and placebo were randomly allocated to 15 matched pairs of patients with motor neuron disease. With validated composite interval scores, this trial excluded a 50% or greater improvement with RX77368 at month 12 in scores of respiratory, lower limb, and activities of daily living function with greater than 90% power, and in bulbar function scores with 80% power. For upper limbs, 52% and 75% improvements were excluded at months 9 and 12 respectively with 80% power. Patients who died during the study had faster deterioration rates in bulbar and respiratory scores than their surviving pairs. The feasibility of screening drugs for significant biological effects with small sample sizes and good statistical power is shown. The difficulties of handling deaths and dropouts when using this design are discussed. Comparisons are made with sample sizes required using other scores and rating scales, as well as with those required in hazard and event rate studies. A simple clinical grading scale for motor neuron disease, with its corresponding composite interval scores, is described.
Effects of a thyrotropin releasing hormone analogue on locomotor and other motor activity in the rat
Neuropeptides, 1985
In the present experiments, locomotion has been studied in rats after injection of TRH analogue RX77368 (lCmg/kg i.p. 1. The measure used was the frequency of the cyclic shifts of weight from side to side (WTF) which accompany the progress of locomotion. It therefore provides an indirect measure of stepping frequency. After injection of RX77368 there was a shift in WTFs towards higher frequencies, i.e. when the rat walked it was taking more steps per second. These results suggest that RX77368 stimulates basic motor patterns associated with locomotion. The results obtained in these experiments are compared with those obtained using different quantification methods for locomotion and there is speculation concerning the possible modes of action of RX77368 including interactions with other neurotransmitter systems.
The role of Thyrotropin Releasing Hormone in aging and neurodegenerative diseases
American Journal of Alzheimer’s Disease, 2013
Thyrotropin releasing hormone (TRH) is primarily known as the central regulator of the hypothalamic-pituitary-thyroid (HPT) axis. However, TRH also exerts a variety of central nervous system effects independent from its activity in the HPT axis. With advancing age, decreases in TRH synthesis, expression, and activity have been demonstrated. Associated with this emerging evidence suggests that TRH is implicated in neurodegenerative diseases of aging, including Alzheimer's disease and Parkinson's disease. TRH and its synthetic analogs have been recognized as trophic factors in neurons of the diencephalon and spinal cord, and as neuroprotectants against oxidative stress, glutamate toxicity, caspase-induced cell death, DNA fragmentation, and inflammation. In this review, we will provide an overview of some of the roles of TRH, outside of the HPT axis, associated with pathological aging and neurodegeneration and we shall discuss the potential of TRH and TRH analogs for the treatment of neurodegenerative diseases.