Use of TRH Analogues in Motorneurone 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
Phase II/III randomized trial of TCH346 in patients with ALS
Neurology, 2007
Background: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. Methods: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). Results: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). Conclusion: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS. Neurology ® 2007;69:776-784 ALS is characterized by progressive weakness leading to death resulting from degeneration of lower and upper motor neurons. At present, the drug riluzole is the only approved disease-specific treatment for patients with ALS. 1 Emerging evidence suggests that apoptosis is an important mechanism of motor neuron degeneration in ALS. 2-4 TCH346 (dibenz [b,f]oxepin-10-ylmethyl-prop-2-ynyl-amine, hydrogen maleate salt) is a novel compound that prevents both the apoptotic increases of the glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and the nuclear accumulation of GAPDH. 5 TCH346 prevents neuronal degeneration in a variety of in vitro and in vivo models of apoptosis and neurodegeneration. 6 The results of a Phase II trial, a safety study (n ϭ 45), and another study in Parkinson disease (PD) suggest that the drug is safe and well tolerated in patients receiving doses of 0.5, 2.5, or 10 mg daily over a 12-week period. 7 The study reported here was designed to evaluate four oral doses of TCH346 compared with placebo as a guide to dose selection for future trials. We used a novel clinical trial design in this study. METHODS Eligible patients were between ages 21 and 80 years and had a clinical and laboratory-supported diagnosis of *The TCH346 Study Group members are listed in the appendix.
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.
Advances in the Treatment of Motor Neuron Disease (Amyotrophic Lateral Sclerosis)
Brain Pathology, 1997
Amyotrophic lateral sclerosis (Charcot's disease) is a degenerative disease of the motor system characterised by the progressive development of muscular weakness due to a combination of lower and upper motor neuron involvement. In the later stages of the disease other disabilities may develop, especially frontal dementia and, sometimes, extrapyramidal features. The extra-ocular muscles, the crico-pharyngeal muscles, the abductor muscles of the larynx, and the striated sphincter muscles of the anal canal and of the urethra, are strikingly spared. The peak age of onset is ifi the sixth decade.
Developments in the treatment of Motor Neurone Disease
2003
Introduction Motor neurone disease (MND) is a progressive neurodegenerative disorder affecting primarily lower motor neurones of the brainstem and spinal cord and upper motor neurones of the cerebral cortex. It is the third most common adult-onset neurodegenerative disease, with an incidence of 1-2 per 100,000. Approximately 5 to 10% of cases are familial. Affected individuals typically develop progressive muscle weakness and wasting that eventually involves both limb and bulbar muscles, combined with upper motor neurone signs such as brisk reflexes and a positive Babinski sign. The disease has a mean age of onset of 55 years. Death usually results from respiratory failure due to weakness of the respiratory muscles, an average of 3 years after onset of symptoms. There are two aims in the treatment of motor neurone disease. The first, as this is an invariably fatal disorder, is the alleviation of symptoms to maintain quality of life. The second is to slow the progression of neuronal ...
IOSR Journal Of Pharmacy And Biological Sciences (IOSR-JPBS), 2019
Motor neuron disease is vary hazards disease in recent time, MND (Motor Neuron Disease) basically it shows clinical presentation to ALS (Amyotrophic lateral sclerosis) considered is most neurodegenerative disease. In MND basically loss of nerves in the spine and brain is not working so it is Refferd to neurodegeneration. It is recorded as in last past year we have seen lots of changes related to patient care treatment improving and drug safety but also rapid scientific advances is there, so that rational therapies based on key pathogenic mechanisms now seem plausible. ALS have both properties in heterogeneous. it occurs 1 year to delay from first symptoms to diagnosis where as half of patient succumb within 3-4 years , although the heterogeneity suggest therapeutic study with respect to clinical study. RNA Process is also implicated and show protein degradation. Apparent clinical heterogeneity tells us that therapeutic studies should include detailed biomarker profiling, they even tell us about the genetic and clinical statistritions. The most common mutation, accounting for 10% of all Western hemispheres ALS due to this protein degradation is occurs. Major part is still not clear how these fundamental is working continuously. This pre-symptomatic study considered is new era or new initiative for neurodegenerative disorders in neurological sciences.
Current Therapy of Drugs in Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS), commonly termed as motor neuron disease (MND) in UK, is a chronically lethal disorder among the neurodegenerative diseases, meanwhile. ALS is basically irreversible and progressive deterioration of upper and lower motor neurons in the motor cortex, brain stem and medulla spinalis. Riluzole, used for the treatment of ALS, was demonstrated to slightly delay the initiation of respiratory dysfunction and extend the median survival of patients by a few months. In this study, the key biochemical defects were discussed, such as: mutant Cu/Zn superoxide dismutase, mitochondrial protectants, and anti-excitotoxic/ anti-oxidative / anti-inflammatory/ anti-apoptotic agents, so the related drug candidates that have been studied in ALS models would possibly be further used in ALS patients.
Journal of Neurology, Neurosurgery & Psychiatry, 1987
Twenty five patients with motor neuron disease completed a double blind randomised cross over trial of RX77368, a stabilised TRH analogue, iv over 2 hours against saline. Temporary improvement in bulbar symptoms including speech, respiratory parameters, tongue movements and swallowing were seen. Fasciculations increased and spasticity decreased. Change in muscle force with drug was different from placebo but both increase and decrease in force were seen and did not result in detectable changes in function. Side effects were clinically significant in 50% of the patients and cleared within 12 hours. Prolonged rise of thyroxine and an increase in plasma levels of prolactin, thyroid stimulating hormone and growth hormone were seen and followed characteristic patterns. Adult sporadic motor neuron disease has an incidence a molar basis on various tests of neuroof about l-l 5/100000' which is of the same order of pharmacological activity, yet its endocrine effect is of magnitude as that of multiple sclerosis.2 Its prevathe. same magnitude.20 21 Its systemic availability is lence, however, is much less than that of multiple four times more than that of TRH and its much sclerosis because about 75% of the patients die within greater neuropharmacological potency possibly 5 years of onset, usually from complications related to relates to slow enzymatic degradation in nervous tisweakness in bulbar muscles.3 sue, 8192223 In humans plasma half life is 1080 Address for reprint requests: Dr RJ Guiloff, Westminster Hospital, 108). Mean age for males was 556 years (range 41-7 1) Dean Ryle Street, Horseferry Road, London SWIP2AP, UK. and for females 628 years (range 52-81). Median time to severe incapacity was 13-5 months (range 5-54). All gave