Thyrotropin-releasing Hormone Tartrate Research Articles

Efficacy of Thyrotropin-Releasing Hormone Analog for Protracted Disturbance of Consciousness due to Aneurysmal Subarachnoid Hemorrhage

The efficacy of thyrotropin-releasing hormone tartrate (TRH-T) for treating prolonged disturbance of consciousness due to aneurysmal subarachnoid hemorrhage (SAH) remains unclear. The purpose of the present study was to determine whether TRH-T was really effective, and what was the recovery factor when it was valid. This was a retrospective study of a single facility. We treated 208 patients with aneurysmal SAH at our hospital between 2011 and 2017. Among them, we investigated 97 cases in which TRH-T was administered to prolonged disturbance of consciousness. Thirty one patients with Hasegawa dementia rating scale-revised (HDS-R) score less than 20 were included. Patients' HDS-R scores were evaluated 7 days after clipping the aneurysm and 2 days after completing a course of TRH-T treatment. HDS-R score increases of greater than or over equal to 8 and less than 8 were defined as good and poor outcomes, respectively. Outcomes were compared to 11 patients who did not receive TRH-T treatment. Average initial and post-treatment HDS-R scores were 9 ± 6.6 and 19 ± 9.5, respectively. The good outcome group included 19 patients. Statistically significant differences in HDS-R score changes were observed between the group with initial HDS-R scores of 0-4 and the other groups. Poor outcomes were significantly correlated with age of greater than 60 years and initial HDS-R scores less than oroverequal to 4 points. The improvement in HDS-R score was significantly greater in the TRH-T administration group than the control group. TRH-T was effective for treating prolonged disturbance of consciousness due to aneurysmal SAH, especially in young patients with HDS-R scores between 5 and 20.

Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes.

Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes.

Efficacy of Thyrotropin‐Releasing Hormone in the Treatment of Intractable Epilepsy

Purpose: Despite rapid advances in the treatment of epilepsy with the introduction of new drugs, the seizures in a number of children with epilepsy remain uncontrollable. Thus a more potent, yet safer therapy is needed. Adrenocorticotropic hormone (ACTH) has been used to treat children with intractable epilepsy, such as West syndrome and Lennox‐Gastaut syndrome. However, ACTH administration is occasionally associated with serious side effects, including immunosuppression, hypertension, and brain shrinkage. Consequently, in this study, the efficacy of an endogenous hormone, thyrotropin‐releasing hormone (TRH), was reevaluated for the treatment of intractable epilepsy. Methods: From 1991 to 1996, we studied the efficacy of TRH‐tartrate (TRH‐T) in 34 children with intractable epilepsy (16 with West syndrome, 11 with Lennox‐Gastaut syndrome, three with localization‐related epilepsies, two with severe myoclonic epilepsy, one with early myoclonic encephalopathy, and one with Angelman syndrome). TRH‐T was administered intravenously or intramuscularly at a dose of 0.05 mg/kg/day once per day for 4 weeks. The subjects were classified into three groups based on the frequency of their seizures and the EEG effects: cessation of seizures and seizure discharges for >1 year (very effective group), a >50% reduction in the frequency of seizures or seizure discharges or both (effective group), and no changes in the frequency of seizures or seizure discharges (ineffective group). Results: There were eight cases in the very effective group, 10 in the effective group, and 16 in the ineffective group. The patients in the very effective group stopped having seizures, including infantile spasms, tonic seizures, atypical absence, atonic seizures, myoclonic seizures, and partial seizures within 11 days to 3 months after the initiation of the TRH therapy. It is noteworthy that no seizures occurred for >3 years in four of the eight cases in the very effective group. The 16 patients with West syndrome comprised five cases in the very effective group, two in the effective group, and nine in the ineffective group. The 11 patients with Lennox‐Gastaut syndrome were subdivided into three cases in the very effective group, three in the effective group, and five in the ineffective group. All three patients with localization‐related epilepsies were in the effective group. Conclusions: TRH should be considered as a possible treatment for Lennox‐Gastaut syndrome and West syndrome, especially for a patient who has an. infection or severe organic lesions in the brain, or who is immunosuppressed. It is noteworthy that TRH is also effective in the treatment of intractable localization‐related epilepsies. The relatively long duration of the action of TRH after the termination of administration may indicate that the mechanism for its anticonvulsant action differs from those of other anticonvulsant drugs.

Involvement of glutamate and γ-aminobutyric acid (GABA)-ergic systems in thyrotropin-releasing hormone-induced rat cerebellar cGMP formation

The increase in cyclic guanosine 3',5'-monophosphate (cGMP) caused by subcutaneous injection of thyrotropin-releasing hormone (TRH) tartrate was observed in a region-specific manner in the rat cerebellum. TRH tartrate (TRH-T) (2.8, 7.0 and 17 mg/kg as free TRH, s.c.) produced dose-dependent increases in cGMP levels markedly in the cerebellar superior and inferior vermis, and a smaller but still significant increase in the cerebellar hemispheres and brainstem but no significant increases in other brain regions. The TRH-induced increase in the cGMP level in the cerebellum was suppressed by pretreatment with muscimol, THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3(2H)-one) or MK-801 (dizocilpine maleate) and partially suppressed by atropine but was not suppressed by chlordiazepoxide, oxazepam, phentolamine, propranolol, cyproheptadine, haloperidol, baclofen or DNQX (6,7-dinitroquinoxaline-2,3-dione), suggesting the possible involvement of GABA (gamma-aminobutyric acid)(A)-ergic, N-methyl-D-aspartate (NMDA)-type glutamatergic and cholinergic systems. These results suggest that excitatory amino acids may be involved in the cGMP formation caused by TRH in the cerebellar areas, and that cGMP formation is inhibited by enhancement of GABAA receptor function.

Alterations in Local Cerebral Glucose Metabolism and Endogenous Thyrotropin-Releasing Hormone Levels in Rolling Mouse Nagoya and Effect of Thyrotropin-Releasing Hormone Tartrate

To identify the brain region(s) responsible for the expression of ataxic gaits in an ataxic mutant mouse model, Rolling mouse Nagoya (RMN), changes in local cerebral glucose metabolism in various brain regions and the effect of thyrotropin-releasing hormone tartrate (TRH-T), together with alterations in endogenous thyrotropin-releasing hormone (TRH) levels in the brains of RMN, were investi gated. Ataxic mice [RMN (rol/rol)] showed significant decreases in glucose metabolism in regions of the diencephalon: thalamic dorsomedial nucleus, lateral geniculate body and superior colliculus; brain stem: substantia nigra, raphe nucleus and vestibular nucleus; and cerebellar nucleus as compared with normal controls [RMN (+/+)]. When RMN (rol/rol) was treated with TRH-T (10 mg/kg, equivalent to 7 mg/kg free TRH), glucose metabolism was significantly increased in these regions. These results suggest that these regions may be responsible for ataxia. We also found that TRH levels in the cerebellum and brain stem of RMN (rol/rol) were significantly higher than those of RMN (+/+). These results suggest that ataxic symptoms in RMN (rol/rol) may relate to the abnormal metabolism of TRH and energy metabolism in the cerebellum and/or brain stem and that exogenously given TRH normalizes them.

Thyrotropin-releasing hormone in treatment of intractable epilepsy: Neurochemical analysis of CSF monoamine metabolites

The efficacy of thyrotropin-releasing hormone in children with intractable epilepsy was investigated and changes in cerebrospinal fluid monoamine metabolites were analyzed. The 18 patients had either West syndrome (12 patients) or Lennox-Gastaut syndrome (6 patients), which was intractable to antiepileptic drug therapy and to adrenocorticotrophic hormone. Thyrotropin-releasing hormone-tartrate was administered for 4 weeks. Before and after the thyrotropin-releasing hormone administration, cerebrospinal fluid was collected and analyzed for 5-hydroxyindoleacetic acid, kynurenine, homovanillic acid, and 3-methoxy-4-hydroxyphenyl glycol. The patients were classified into 3 groups, based on seizure frequency and electroencephalographic effects: cessation of seizures and seizure discharges (very effective; group A), reduction of seizures and/or seizure discharges (effective; group B), and no changes in frequency of seizures or discharges (not effective; group C). There were 6 patients in group A, 3 in group B, and 9 in group C. There were no significant differences in monoamine metabolites before and after the thyrotropin-releasing hormone therapy. A trial of thyrotropin-releasing hormone for the treatment of intractable epilepsy is warranted and further study is required on the mechanism of the antiepileptic action of thyrotropin-releasing hormone.

Pilot study of short-term thyrotropin-releasing hormone treatment in stabilized focal cerebral ischemia: a pharmacoencephalographic study

Abstract Quantitative electroencephalography (q-EEG) was carried out in 20 patients, who had suffered from a single ischemic stroke 1 to 3 months prior to commencement of the study, before (T0) and after 14 days of treatment wih thyrotropin-releasing hormone tartrate (TRH-T) 4 mg/day or placebo (T1), and 7 days after drugs suspension (T2). TRH-T and placebo treatments did not show any statistically significant effect on q-EEG. Nevertheless, TRH-T showed a trend toward decreased delta and theta relative power intensity (RPI) and toward increased alpha RPI. This pattern was clear at T1 and was still evident at T2. Power spectral analysis of TRH-T treated stroke patients showed a shift of alpha peak from 8.5 Hz at T0 to 9.0 Hz at T1 and to 8.63 Hz at T2. These features suggest that TRH-T behaves as a psychoactive drug after short-term administration in patients with chronic cerebrovascular disease.

リュープリン（高活性ＬＨ−ＲＨ誘導体）の研究開発

Biologically active peptide have potential therapeutic applications in the treatment of diseases caused by peptide deficiency. However, there are only a few peptide drugs, Elcitonin (a calcitonin derivatives for osteoporosis, Asahikasei), Hirutonin (TRH tartrate for prolonged disturbance of consciousness, Takeda) and Leuplin (a highly potent LH-RH derivative for prostate cancer/endometriosis, Takeda) There are two serious drawbacks to using peptide derivatives as drugs : their poor oral bioavailability and their short duration of activity. Although the latter can be overcome by studing various derivatives, the development of orally active peptide derivatives is almost impossible. I would like to describe briefly the process of the research and development of “Leuplin Depot”, once-a-month depot type formulation of super agonist of LH-RH.

Effects of TRH-T on spinal motoneurones in man.

The effect of thyrotropin-releasing hormone tartrate (TRH-T) on the decrease in H Max/M Max ratio, an index of the spinal motoneurone pool, induced by haloperidol, was studied in 15 healthy volunteers. In all subjects, the H response was examined by an electromyographic apparatus. The values were expressed as H Max/M Max ratio, that gives an index of excitability of the spinal motoneurone pool. It was found that the mean H Max/M Max ratio value significantly decreased after haloperidol administration, but this effect was completely reversed by the injection of TRH-T. This finding suggests that the peptide may modulate motoneurone functions.

Thyrotropin releasing hormone (TRH) and its analog, RGH-2202, accelerate maturation of cerebellar neurons in vitro

We have studied the "trophic" action of thyrotropin releasing hormone (TRH) in cultured cerebellar granule cells, a pure and homogeneous population of glutamatergic neurons. As an index of neuronal maturation, we have measured the uptake of D-[3H]aspartate (a non-metabolizable analog of glutamate) at different days of maturation in vitro (DIV). In control cultures, D-[3H]Aspartate increased linearly during maturation reaching plateau values between 7 and 9 DIV; daily addition of TRH tartrate (TRH-t) or RGH-2202 (a TRH analog) accelerated in a concentration-dependent manner the maturation profile of D-[3H]aspartate uptake. This effect was more pronounced for RGH-2202: in cultures treated daily with RGH-2202, D-[3H]aspartate uptake was fully expressed after 3 DIV. Neither TRH-t nor RGH-2202 significantly increased D-[3H]aspartate uptake in mature cells, excluding a direct action on the glutamate transport system. Both compounds specifically potentiated the increase in [3H]inositol monophosphate formation (but not the stimulation of 45Ca2+ influx) induced by N-methyl-D-aspartate (NMDA) receptor agonists, without affecting the stimulation of inositol phospholipid hydrolysis by quisqualate or carbamylcholine. We suggest that, in cultured cerebellar granule cells, TRH and RGH-2202 enhance the trophic action of endogenous glutamate by amplifying some of the intracellular events that follow the influx of extracellular Ca2+ through NMDA-gated ion channels.

Effects of Tartrate Thyrotropin -Releasing Hormone Treatment on Serum Thyrotropin, Free Triiodothyronine, Free Thyroxine and Prolactin Levels in Patients with Spinocerebellar Degeneration

The aim of the present study was to investigate the pituitary-thyroid axis function during the long-term (30 days) intramuscular administration of 4 mg/day of thyrotropin-releasing hormone tartrate (TRH-T) in 15 patients with spinocerebellar degeneration. The study was performed as follows: (1) acute 4 mg TRH-T test with hourly prolactin (PRL) and thyroid-stimulating hormone (TSH) level evaluations for 6 h; (2) placebo; and (3) 4 mg/day of TRH-T administration for 30 days with TSH, PRL, and free T3 and T4 (FT3 and FT4) levels evaluated on days 1, 15 and 30. Hormone determination was performed just before and 1 h after placebo or TRH-T administration. The acute administration of TRH-T caused a sustained rise of TSH which lasted until the 6th hour and of PRL which declined after 1 h (p < 0.01). During placebo administration, no change of TSH, PRL, FT3 or FT4 was observed. On the 1st day of treatment, 1 h after the TRH-T injection, a significant increase of both TSH and PRL levels occurred (p < 0.01). As compared to the 1st day, a significant decrease of the TSH (p < 0.01) levels occurred on the 15th and 30th days before TRH-T: the TSH response to TRH-T administration was present although less than on the 1st day (p < 0.01). Moreover, throughout the whole period of treatment, no difference was recorded for PRL levels before or after TRH-T administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent vagal fibres and central cholinergic mechanisms are involved in the TRH-induced reversal of haemorrhagic shock

In a model of haemorrhagic shock causing the death of all saline-treated rats within 25.8 +/- 2.7 min after treatment, the intravenous injection of thyrotropin-releasing hormone tartrate (TRH-T) at the dose of 4 mg/kg induces a prompt and sustained increase of arterial pressure and pulse amplitude, with survival of all rats. Bilateral vagotomy, atropine sulphate (2 mg/kg intraperitoneally) and hemicholinium-3 (20 micrograms/rat intracerebroventricularly) partially prevent the TRH-T-induced shock reversal, whereas atropine methylbromide has no effect. These data indicate that afferent vagal fibres, brain cholinergic neurons and central muscarinic receptors play a role in the mechanism of the anti-shock effect of TRH-T.

TRH reverses the ECG and EEG ischemic changes induced by massive hemorrhage in rats

In a rat model of volume-controlled hemorrhagic shock causing the death of all saline-treated animals within 30 min of treatment, the intravenous bolus injection of thyrotropin- releasing hormone tartrate (TRH-T) at the dose of 4 mg/kg induced the prompt and sustained disappearance of the ECG and EEG signs of heart and brain ischemia, along with the reversal of hypotension and respiratory depression and with 100% survival rate at the end of the 2 h observation period. These data confirm that, in a pre-terminal condition induced by massive hemorrhage, timely treatment with TRH-T will restore heart and brain perfusion to levels compatible with survival and with functional recovery from ischemia and maintain it at those levels for some hours.

Long-Term Intramuscular Administration of Thyrotropin-Releasing Hormone Tartrate in Patients with Cerebrovascular Disease: Effects on the Pituitary-Thyroid Axis

We studied the effects of long-term (30 days) refracted daily intramuscular administration of 4 mg TRH tartrate (TRH-T) on the pituitary-thyroid axis in 20 euthyroid patients affected by cerebrovascular disease (CVD). All subjects were assayed for T4, T3, FT4, FT3, TSH and TBG plasma levels before treatment (D0), after 15 and 30 treatment days (D15, D30), and after a 15-day washout (D45). In addition, TSH response to 200 micrograms intravenous TRH was assessed at D0, D30 and D45. We observed a significant increase in T4, FT4 and FT3 levels in the face of decreased TSH concentrations. A blunted TSH response to TRH bolus persisted at D30. These data demonstrate that the down-regulation mechanism may be partially overcome in vivo when thyrotrophs are chronically exposed to pharmacological TRH-T doses and that TSH pattern is mainly due to the negative feedback of thyroid hormones, even though pituitary TSH reserves may become depleted. Furthermore, prolonged TRH-T administration does not produce hyperthyroidism in euthyroid CVD patients.

Intestinal absorption mechanisms of thyrotropin-releasing hormone.

Intestinal absorption mechanisms of thyrotropin-releasing hormone (TRH) following the oral administration of TRH-tartrate (TRH-T) were studied in animals. When TRH-T was orally administered to rats or beagle-dogs, absorption of TRH showed apparent saturation and decreased with food ingestion. TRH is very stable against gastrointestinal digestive enzymes, homogenized intestine and epithelial cells. First pass effect in the liver was not observed in beagle-dogs. Absorption site specificity was found in rats, namely TRH can be absorbed from only the upper part of the small intestine. A saturation phenomenon was also observed in in situ and everted sac experiments. TRH absorption was inhibited by the existence of oligopeptides and some beta-lactam antibiotics that had been reported to be absorbed by active transport or carrier-mediated transport systems. The transfer of TRH from mucosal to serosal solutions was inhibited by the replacement of medium Na ions by K ions and by the existence of oligopeptides. The transfer rate from serosal side to mucosal side was much slower than that from mucosal side to serosal side. These results suggested that there should be a certain carrier-mediated transport system in the absorption process of TRH.

Absorption of thyrotropin-releasing hormone after oral administration of TRH tartrate monohydrate in the rat, dog and human.

Quantitative blood levels of thyrotropin-releasing hormone (TRH) were determined by a sensitive and specific radioimmunoassay after oral administration or intravenous injected of thyrotropin-releasing hormone tartrate monohydrate (TRH-T) in the rat, dog and human. A pharmacokinetic analysis after intravenous injection of the drug revealed biphasic elimination of the whole blood concentration following a two-compartment open model with a half-life in alpha-phase of 2.6 min and beta-phase of 4.6 min in the rat (dose: 500 micrograms/kg); a half-life in alpha-phase of 3.2 min and beta-phase of 18.1 min in the beagle-dog (dose: 146 micrograms/dog); a half-life in alpha-phase of 4.0 min and beta-phase of 20.4 min in the human (dose: 730 microgram/human). The absolute bioavailability of TRH after oral administration of TRH-T solution in 24 h fasting rats were 1.5, 0.4, and 0.2% at 29.2, 146, and 730 mg/kg dosing levels, respectively (e.q. 20, 100, 500 mg/kg of TRH) compared with i.v. injection (dose: 500 microgram/kg). In beagle-dogs, they were 12.6, 9.8, 5.6, and 3.5% at 2.92, 14.6, 29.2, and 146 mg/dog dosing levels, respectively (e.q., 10, 20, and 100 mg/dog at TRH) compared with i.v. injection (dose: 146 micrograms/dog). Those of after meal in beagle-dogs were 6.0 and 2.3% at 2.92 and 29.2 mg/dog dosing levels (e.q. 2, and 20 mg/dog of TRH). Thus, TRH absorption showed apparent saturation and was decreased by food ingestion. The absolute bioavailability in the humans, who were administered 11.7 mg TRH-T (2.92 mg/tablet X four, e.q. 8 mg of TRH) two hours after meal, was 2.0% on the average, and thyroid stimulating hormone levels were significantly increased by oral administration of TRH-T tablets.

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

The clinical efficacy, dose-response relationship, and safety of TRH-T (thyrotropin releasing hormone tartrate) were assessed in 290 patients with spinocerebellar degeneration (SCD) in a 2-week, double-blind study using placebo as control. 254 patients satisfied the criteria for inclusion in evaluation of the drug efficacy. The patients were treated with TRH-T in an intramuscular dose of 2 mg, 0.5 mg or 0 mg (placebo) as TRH once a day for 2 weeks. Clinical responses to these treatments were evaluated 3 times: at the end of weeks 1 and 2 of treatment and a week after the end of treatment. The results of "global improvement rating" as well as those of "ataxia improvement rating" showed that both 2 mg and 0.5 mg TRH-T treatments were significantly superior to placebo treatment in patients with predominantly cerebellar form of SCD. The effect was well maintained a week after the end of the 2-week treatment in the patients who were given TRH-T in daily dose of 2 mg and showed improvement at the end of treatment. The results of "improvement rating of each symptom" revealed that 2 mg treatment was significantly more effective than placebo for disorders of standing, gait, speech and writing. In the patients who had no pyramidal involvement or disorder of deep sensation, the drug efficacy and dose-response relationship were evident. Adverse reactions to the drug such as headache, feeling febrile and nausea were observed in 50% of the patients on 2 mg treatment, in 38% of those on 0.5 mg treatment and in 21% of those on placebo patient, however, discontinued treatment because of adverse reactions.

Anti-epileptic effects of TRH-T and DN-1417.

Antiepileptic effects of both TRH tartrate (TRH-T) and its derivative, γ-butyrolactone-γ-carbonyl-L-histidyl-L-prolinamide citrate (DN-4417) have been evaluated using the amygdaloid kindling cat preparation. The results reported are: 1) transient anticonvulsant effects unrelated to dose for both TRH-T and DN-1417, 2) long-term elevation of the final electroconvulsive threshold in some cats after TRH-T and DN-1417 treatment, 3) prophylactic effects on kindling seizure development as well as effects to prevent positive transfer of the kindling to the contralateral amygdala after daily treatment with DN-1417, 4) a shortened postictal behavioral depression and EEG silence with DN-1417 and 5) a prolonged postictal seizure inhibition period with DN-1417. It is hypothesized that endogenous TRH inhibits seizure activity and reduces the establishment of epileptogenesis in the brain.

Experimental and clinical studies on thyrotropin releasing hormone tartrate (TRH-T) for treatment of disturbances of consciousness (author's transl)

Thyrotropin releasing hormone tartrate (TRH-T) has been found to activate the central nervous system and its pharmacological role has recently received much attention. We studied the effects of TRH-T on EEGs of rat's brains of with isolated perfusion undergoing temporary ischemia. Its clinical effect on persistent disturbance of consciousness was also examined in 38 cases of brain tumor, cerebrovascular disease, head injury, normal pressure hydrocephalus and infectious brain disease. The following results were obtained. 1. TRH-T was found to improve EEGs of rat's brains with isolated perfusion undergoing temporary ischemia. 2. Beneficial clinical responses to TRH-T therapy were observed in 81.6% of the patients with persistent disturbances of consciousness due to brain tumors, cerebrovascular disease, head injury, normal pressure hydrocephalus or infectious brain disease. Among the responses, 26.3% was rated as excellent, 5.3% as good, and 50.0% as fair. 3. The therapeutic efficacy was found to be higher in patients with shorter durations and shorter fixed periods of disturbed consciousness, and in patients with relatively wild disturbances of consciousness at the start of therapy. 4. No noteworthy side effects or changes in data from hematological examinations, blood chemistry tests and urinalyses were observed.

Molecular conformation of thyrotropin-releasing hormone from the X-ray structural analysis of its tartrate

An X-ray crystal study of thyrotropin-releasing hormone tartrate has revealed that its molecular structure, in contrast with predictions based on energy calculations and n.m.r. spectroscopic studies, contains an extended peptide bond stabilized by a hydrogen bond between the π-NH unit of histidine and the carbonyl oxygen of the proline amide.