Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence that thyrotropin-releasing hormone (TRH) has prominent trophic effects on the motor system led to several negative therapeutic trials in amyotrophic lateral sclerosis, a disease of the motor system. Since TRH crosses the blood-brain barrier poorly, if at all, we postulated that the negative parenteral clinical trials could be a result of insufficient drug-receptor interaction. We thus carried out a blinded, placebo-controlled, crossover study of intrathecal TRH in 36 patients by delivery through an implanted, constant infusion pump achieving a steady-state CSF level comparable with that shown to be effective in tissue culture experiments. Utilizing a quantitative measurement technique to assess motor unit loss, we did not observe any alteration of the progressive course during 6 months on TRH and 6 months on saline placebo. However, the implanted pump delivery system proved to be safe, reliable, and well tolerated.
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PMID:Intrathecal thyrotropin-releasing hormone does not alter the progressive course of ALS: experience with an intrathecal drug delivery system. 157 28

13 patients with amyotrophic lateral sclerosis (ALS) were treated with intravenous infusion of thyrotropin-releasing hormone (TRH). In 6 patients 2 mg/day of TRH was i.v. given over 2 hours for 10 days. In 7 others 2 mg/day of TRH was continuously infused by means of a pump. An increase of thyroid hormones related to the duration of the treatment was observed. A surprising finding was the onset of prolactin (PRL) response to growth hormone releasing hormone (GHRH), previously absent.
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PMID:Amyotrophic lateral sclerosis: thyroid and prolactin hormone changes in thyrotropin-releasing hormone therapy. 212 25

We studied the trophic effects of various neuropeptides, including substance P (SP), thyrotropin-releasing hormone (TRH), neurotensin (NT) and bombesin (BN) on explanted cultures of ventral spinal cord from 13- to 14-day-old rat embryos. In groups, receiving one type of drug only, there was a significant neurite-promoting effect (NPE) in SP, TRH and BN-treated cultures. At a concentration of 10(-12) M the most potent effect was shown by SP. However, BN had the most potent action at concentrations greater than 10(-10) M. It also became clear that there were maximum and minimum effective concentrations for these 3 neuropeptides. NT had no NPE at any concentration. There was no additional NPE when any two or all four of these neuropeptides were given simultaneously. Our results demonstrate that BN, SP, and TRH have a trophic effect on ventral spinal cord in cultures, and may contribute to a therapeutic strategy in amyotrophic lateral sclerosis.
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PMID:Trophic effect of various neuropeptides on the cultured ventral spinal cord of rat embryo. 247 30

Protirelin (thyrotropin-releasing hormone) appears to be a neuromodulator in the extrahypothalamic nervous system and has been suggested as an adjunct in the treatment of amyotrophic lateral sclerosis (ALS). Clinical studies have been divided on the efficacy of protirelin (TRH) despite strong experimental findings that are consistent with a role for the peptide in ALS. Recent findings provide evidence of a gender-related specificity in the ability of protirelin to potentiate the monosynaptic reflex. While castration in male neonatal rats lowered the sensitivity to protirelin, testosterone treatment restored that sensitivity. An examination of the clinical studies reveals a failure either to identify patients' sex or to separate the results on the basis of sex. These findings provide convincing evidence for the potential efficacy of protirelin in ALS if the patient's sex and underlying hormonal status are taken into account.
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PMID:Protirelin (thyrotropin-releasing hormone) in amyotrophic lateral sclerosis. The role of androgens. 256 37

We used quantitative autoradiography to determine the density of thyrotropin-releasing hormone (TRH) receptors in discrete regions of spinal cord from four patients with amyotrophic lateral sclerosis (ALS). The density and distribution of [3H]-3-methyl-histidine-TRH binding to TRH receptors differed from reported values in normal individuals, with fewer TRH receptors in lamina II and lamina IX. The diminished concentration of TRH receptors in lamina IX may reflect the loss of motor neurons in ALS.
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PMID:Autoradiographic localization of thyrotropin-releasing hormone receptors in amyotrophic lateral sclerosis spinal cord. 299 61

We performed double-blind crossover trials to assess the effects of thyrotropin-releasing hormone (TRH) on amyotrophic lateral sclerosis patients. For acute intravenous trials, 500 mg TRH or placebo with norepinephrine was given at 1-week intervals (16 patients). CSF TRH concentration increased, and clinical side effects appeared with TRH. For chronic studies, 25 mg TRH and a saline placebo were given subcutaneously every day for 3 months (25 patients). CSF TRH level increased 29-fold after a single TRH injection, and mild transient side effects occurred. Vital signs, respiratory function, semiquantitative and quantitative neurologic function, muscle strength by manual and dynamometer testing, and EMG were studied. With daily TRH, 10 patients noted subjective improvement without objective evidence, and 10 patients complained of worsening of the disease with objective decline after TRH was stopped. Statistical analysis, however, showed no beneficial effects from either acute or chronic TRH trials.
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PMID:Amyotrophic lateral sclerosis: effects of acute intravenous and chronic subcutaneous administration of thyrotropin-releasing hormone in controlled trials. 308 Jun 95

In spinal cords from seven amyotrophic lateral sclerosis (ALS) patients and four controls, we found no difference in thyrotropin-releasing hormone (TRH) concentration relative to protein content, but there was a reduction per tissue wet weight in ALS. Immunohistochemical localization of TRH in ALS cord was unaltered. Histidyl proline diketopiperazine (HisPro-DKP), a possible metabolite of TRH, was significantly elevated per protein content in ALS. CSF levels of TRH and HisPro-DKP were unchanged. These findings suggest that TRH neurons are not primarily affected in ALS, but TRH and tissue protein are lost together as the disease progresses.
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PMID:Amyotrophic lateral sclerosis: thyrotropin-releasing hormone and histidyl proline diketopiperazine in the spinal cord and cerebrospinal fluid. 309 30

Concentrations of thyrotropin-releasing hormone (TRH) were measured by a specific radioimmunoassay in the brain of 11 patients with amyotrophic lateral sclerosis (ALS) and 6 controls (myocardial infarction, gastric cancer, multiple myeloma, cerebrovascular disease, amyloid neuropathy). TRH was found in all parts of the dissected brain tissues (pedunculus cerebri, corpus callosum, capsula interna, motor area) in patients with ALS and controls. The TRH concentrations in the brain of patients with ALS were significantly lower in the pedunculus cerebri, compared with controls, and tended to decrease in the motor area and corpus callosum, but not significantly. Changes in TRH concentrations did not always correlate with pathohistological changes. These findings suggest that TRH is widely distributed in the human brain and decreases in some part of the ALS brain.
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PMID:Concentrations of thyrotropin-releasing hormone in the brain of patients with amyotrophic lateral sclerosis. 309 27

An investigation of the efficacy of thyrotropin-releasing hormone in amyotrophic lateral sclerosis included study of the intrathecal pharmacokinetics of this neuropeptide. Its mean elimination half-life in CSF was 0.90 hours and was monoexponential. During a 2-hour infusion, 2.75% crossed the CSF/blood-brain barrier. Infusion for 12 months with an implanted pump in three patients at a rate of 3 mg/24 hr resulted in a mean CSF steady state of 2.88, 2.42, and 2.74 micrograms/ml, respectively. Pharmacokinetic data were similar at 6 and 12 months. This is an effective system with potential uses in the treatment of other degenerative diseases.
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PMID:Pharmacokinetics of intrathecal thyrotropin-releasing hormone. 310 19

Thyrotropin-releasing hormone has been reported to increase strength in patients with amyotrophic lateral sclerosis (ALS). DN-1417 is an analog of thyrotropin-releasing hormone, which has less endocrinologic activity, but more anterior horn cell stimulating effect (with no "autorefractory state"). However, 2 mg DN-1417, IM twice a day for 1 month in an open-label trial, produced no objective improvement of strength in nine patients with ALS. No patient entered the double-blind, placebo-controlled phase of the trial.
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PMID:Treatment of amyotrophic lateral sclerosis with the TRH analog DN-1417. 310 20


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