Taltirelin Tanabe Seiyaku William M Brown

1389

Taltirelin Tanabe Seiyaku William M Brown Address Restoragen Inc 4130 NW 37th Street Lincoln NE 68524 USA Email: [email protected]

Originator Tanabe Seiyaku Co Ltd

IDrugs 2001 4(12):1389-1400 @ PharmaPress Ltd ISSN 1369-7056

Action TRH agonist

Status Launched Indication Neurodegenerative disease, Dementia, Alzheimer's disease

Biotechnology Hormone, Peptide Taltirelin (TA-0910), a synthetic thyrotropin-releasing hormone (TRH) analog, has been developed by Tanabe Seiyaku for the treatment of neurodegenerative diseases [154099], [263997]. An NDA was filed in Japan in April 1999 for the treatment of spinocerebellar degeneration (SCD) [296442] and was approved in July 2000 [391719]; the drug was launched in Japan in September 2000 [382555], [383484]. It is the first orally administered drug for this indication [382555]. In September 2001, UBS Warburg (Japan) stated that total sales of taltirelin in 2000 were ¥3.5 bn, and estimated that sales in 2001 would reach ¥7.6 bn, rising to ¥8.6 bn by 2005 [433991]. Also in this month, Morgan Stanley predicted that there would be sales of ¥8 bn in 2001, rising to ¥10 bn in 2002 [422782].

Synonyms and Analogs TA-0910, Ceredist CAS L-Prolinamide, N-[(hexahydro-1-methyl-2,6-dioxo-4pyrimidinyl)carbonyl]-L-histidyl-, (S)Registry No: 103300-74-9 N

HN O H N

O

N N H

H3C

N

O O

NH2

O

Introduction Thyrotropin-releasing hormone (TRH, p-Glu-His-Pro-NH2), was originally isolated and characterized from porcine and ovine hypothalamus in the late 1960s; events leading to its discovery have been chronicled by Reichlin [433363]. TRH also has a wide distribution outside the hypothalamus and is now known to have many endocrine and CNS effects [246766], [433362], [433364], [433365]. Human patients have been characterized with TRH deficiencies [433425], [433426], and a TRH-secreting cancer [433424]. Despite much early controversy on the biosynthesis of TRH [433366], it is now clear that TRH is proteolytically released from a much larger precursor molecule, made in the normal way on a ribosome [433366], [433368], [433370]. Additionally, a C-terminal amidating activity has been characterized in rat hypothalamus [433373]. The TRH prohormone is a protein of approximately 26 kDa that is proteolytically processed to yield TRH, extended forms of TRH and several other non-TRH peptides [433374].

in AD and TRH is known to stimulate this system [433394]. Additionally, the TRH-evoked activation of the sympathetic nervous system is apparently attenuated in men with earlyonset AD [433390] and there is a blunted response to TRH in AD patients [433396].

In addition to its endocrine function, TRH has many CNSmodulating properties. Prior to September 2000, TRH injection was the only drug therapy for the treatment of spinocerebellar degeneration (SCD), a neurodegenerative disease with symptoms such as ataxia due to degeneration of the cerebellum or spinal cord [382555]. TRH has also been studied and used experimentally in treating amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). In treating ALS, TRH improved muscle strength and spasticity [433377]. However, its clinical value remains controversial; several placebo-controlled, double-blind trials showed no statistical benefit [433382], [433385].

The very short biological half-life of TRH itself, as low as 4 to 5 min [433402], [433403], [433404], clearly points to the need for analogs with a longer duration of action for pharmaceutical use. TRH is degraded by enzymes in plasma and hypothalamic tissue. There is wide species variation in TRH degradation, so caution should be exercised in interpreting animal studies [433405]. TRH is degraded by at least three enzymes [433404], including a specific TRHdeaminase, leaving the free acid, Pyr-His-Pro. It is also degraded by a TRH-specific pyroglutamyl aminopeptidase in the blood, to produce the dipeptide, His-Pro-NH2, which cyclizes to form histidyl-proline diketopiperazine, a molecule that apparently has a pharmacology all of its own [433407]. Additionally, there is a histidyl-proline imidopeptidase, which releases prolinamide, Pro-NH2, from the dipeptide Pyr-His.

Several human experiments with TRH in AD have been conducted [261882], [262193], [262184], [262192], [262189], [433388], [433392], [433393]. The cholinergic system is decreased

TRH and its analogs have also been studied in the treatment of epilepsy, schizophrenia, and depression. TRH has been reported to possess anti-epileptic properties in spontaneously epileptic rats [39503], in the rat kindling model of epilepsy [433397], [433398], in Lennox-Gastaut syndrome [433399], and severe childhood epilepsy [433400]. However, its very short duration of action has limited its use and stimulated the search for stable analogs. TRH and its analogs has been extensively tested in schizophrenia, but results, however, have been mixed or contradictory [433401].

1390 IDrugs 2001 Vol 4 No 12

Figure 1. TRH analogs. H N

O

O

OH O O

HN

OH

O

O

NH

HO O

O

NH2

O

CH3 N

CH3

O NH N RX-77368 (Reckitt & Coleman)

N

O O

HN O H2N

NH N

montirelin (Grunenenthal/Nippon Shinyaku)

N

CH3 O O

N

N H

N O

N O

S

H N

N H

H N

H N

NH2

O H N

N

orotirelin

O H N

O N

O

MK-771 (Merck & Co)

Synthesis and SAR Because of the known effects of TRH, many attempts have been made to prepare analogs that might separate its multiple effects and be more resistant to degradation [35022], [185784], [244250], [262186], [433390], [433414]. Analogs (see Figure 1) have been synthesized with modifications to the pyroglutamic acid (p-Glu) moiety (eg, DN-1417 from Takeda, orotirelin, and montirelin from Gruenenthal/Nippon Shinyaku), the Pro residue (eg, RX77368, Reckitt & Coleman) and to both terminal residues (eg, MK-771, Merck & Co). Analogs with 6-membered rings in place of the p-Glu moiety of TRH itself are more than 40-fold more potent as CNS agents, at least in part, because of resistance to degradation [35019]. The synthesis and properties of many TRH analogs have now been reported [244250], [262202], [310641], [310718], [310719], including MK-771 [226125], montirelin [196152], DN-1417 [244254], RX-77368 [217171], azetirelin (Yamanouchi) [215581], and posatirelin (Richter Gedeon) [247372]. In terms of CNS effects, taltirelin (TA-0910) was the most potent of a series of analogs synthesized at Tanabe [35019], [273705]. It was synthesized by methylating 4,5dihydroorotic acid benzyl ester with methyl iodide. The 1methyl derivative was then debenzylated by hydrogenolysis, using hydrogen over a palladium/carbon catalyst. The resulting (S)-1-methyl-4,5-dihydroorotic acid was condensed with L-histidyl-L-prolinamide, using dicyclohexylcarbodiimide and N-hydroxysuccinimide in dimethyl-formamide [35019], [35022]. Suzuki and colleagues screened the numerous TRH analogs prepared for activity in antagonizing reserpine-induce hypothermia, antagonizing pentobarbital-induced anesthesia, and in stimulating spontaneous locomotor activity, all in mice [35019]. Taltirelin was 60-fold more potent than TRH in the spontaneous locomotor activity assay, almost 90-fold more potent in the reserpine-induced hypothermia assay, and almost 30-fold more potent in antagonizing pentobarbitalinduced anesthesia [35019], [273705]. The methyl group at the 1-position was key to this CNS activity. Analogs with ethyl, allyl, isopropyl, and benzyl groups at this position were all more active than TRH, but all much less active than

NH2

O

S

NH2

H N O

O

DN-1417 (Takeda)

H N

O

N

N H O

O

H3 C O

HO

N

N

N H O

NH2

CH3

H N

O N H H

O N NH2

O

H

O azetirelin (Yamonouchi)

posatirelin (Richter Gedeon)

taltirelin. Additionally, diastereomeric derivatives of taltirelin have been prepared and compared with the parent compound; very low activities were observed in the CNS assays. Thus, it seems the S-configuration of both the 1methyl-4,5,-dihydroorotyl and L-histidinyl-L-prolinamide moieties are crucial for CNS activity [35019]. Much work has also been done to define the pharmacophore of the TRH receptor [262238], [310717], [417383]. Crystal and solution structures of TRH have also been reported [433408], [433410]. The TRH receptor has been cloned and sequenced [262252], and identified as a member of the 7transmembrane-spanning G protein-coupled receptor family [246765], [310717], apparently expressed from a single receptor gene [433411], [433496]. Taltirelin downregulates this receptor [248818], which has been mapped in the brain of the rolling mouse Nagoya (RMN) [241500], an animal model of ataxia in which taltirelin has positive effects [175704], [192744], [241501] , [248809], [248811]. The distribution of the TRH receptor differs in man and rats and is altered in schizophrenics, where there is a significant increase in receptor density in the molecular layer of the dentate gyrus [433387]. In rat brain, TRH receptor enrichment is seen in many regions, including the lateral and cortical amygdaloid nuclei, ventral dentate gyrus, nucleus accumbens, medial septum, piriform cortex, paraventricular thalamic and hypothalamic nuclei, preoptic area, diagonal band of Broca, and lateral septum [433397], [433414], [433415].

Pharmacology Increases in spontaneous locomotor activity observed in mice and rats treated with taltirelin [35025] were inhibited by haloperidol and α-methyl-p-tyrosine, suggesting that taltirelin enhances dopamine (DA) neurotransmission [35025], [248826], [248828], although this has been questioned [262280]. DA is also believed to be involved in the activity of taltirelin in suppressing the preference for alcohol in alcohol-preferring rats [157450], [176564], [248812], [248814], [248818], [310714]. Several studies have examined the effects of taltirelin on circulatory variables [322030], [323760], [323761], [338378].

Taltirelin Brown 1391

Taltirelin potentiates ACh-induced neuronal excitation in rat cerebral cortex neurons, and inhibits ACh-induced desensitization [35022], [234108], [248823]. Taltirelin (0.1 to 1 mg/kg ip) caused a marked dose-dependent increase in extracellular ACh levels and a decrease in choline levels in the hippocampus of freely moving rats. The effects were significantly stronger and longer lasting than the similar effects of TRH [234108]. At doses of 1 and 3 mg/kg ip, taltirelin depressed choline accumulation in the cerebral cortex and hippocampus of γ-butyrolactone-treated rats; moreover, taltirelin increased the accumulation rate of ACh in these regions in rats treated with physostigmine (1 mg/kg ip). TRH (30 mg/kg ip) affected ACh accumulation only in the hippocampus of the γ-butyrolactone-treated rats. These results suggest that taltirelin not only enhances the release of ACh, but also accelerates the ACh turnover (ie, ACh release and synthesis) at the cholinergic neuronal terminals in normal rats [234108]. In addition, taltirelin ameliorated ataxia in RMN (1 to 10 mg/kg/day), in which it was 200- to 300-fold more potent than TRH with effects lasting for up to 3 weeks after the administration period [175704].

effects on food consumption were seen in any dams in a teratogenicity study in pregnant Japanese white rabbits [310666]. Those animals receiving the highest dose showed rapid breathing and temporarily decreased body weight gain. No adverse effects were seen in the fetuses [310666]. Similarly, no teratogenic effects were observed in a study in pregnant Wistar rats, F1 offspring, or F2 fetuses [310673]. Dams receiving the highest dose (15 mg/kg) exhibited wet dog shaking and hyperlocomotion. No adverse effects were seen on reproductive function in pregnant Wistar rats at doses of up to 15 mg/kg [310675].

Metabolism

Gross behavioral effects caused by taltirelin have been studied in mice, rats, rabbits, and dogs [283362], [310638], [327031]. In rats and mice at doses of 10- to 100-fold the pharmacological dose, hyperlocomotion, tail elevation, salivation, piloerection, tremor and increased respiratory rate were seen. In rats, wet dog shakes were also observed. In dogs, increased wakefulness was observed and in rabbits, increased body temperature was noted [283362].

It is believed that the extended duration of action of taltirelin is a result of its resistance to the normal TRH-degrading enzymes [35018], [35024], [241501]. Kinoshita and colleagues reported some pharmacokinetic data in mice [241501]. In animal experiments, intraperitoneal and intravenous doses have proved effective [35020], [175706]. In human experiments reported to date, taltirelin has been administered orally [166359], [241502], [248816], [262259], [262261]. Taltirelin can be conveniently measured in biological fluids using a radioimmunoassay [166356], [241501], [289191]. Studies on the absorption, distribution, metabolism, and excretion in rats and dogs have been published [310739], [310740], [310741]. Intestinal absorption is decreased in fed animals [310739], this was also observed in phase I studies [310644]. The drug is excreted in the urine within 48 h [310739], but no gender-related difference in pharmacokinetics or renal excretion was observed [310740]. The drug does transfer into the brain [310741] and into both the fetus and milk, but only to a slight degree [310740]. Taltirelin has a t½ of approximately 3 h in blood, compared to 5 min for TRH; in the brain the t½ is approximately 1 h, compared to 8 min for TRH [310741].

Toxicity Taltirelin is well tolerated; oral doses of 10 or 20 mg [241502], 2.5 to 20 mg [166358], 5 mg/day for up to 14 weeks [262259], [310689], 10 mg/day for up to 52 weeks [310711], or 10 to 40 mg/day [166359] have been tolerated without serious adverse effects. Several animal toxicity studies have been published [276248], [276324], [310661], [310666], [310673], [310675]. In a perinatal and postnatal toxicity study in Sprague-Dawley rats [310661], dams receiving the highest dose (15 mg/kg) exhibited wet dog shaking during gestation. However, no adverse effects were observed in body weight gain, food consumption, or reproductive performance. The F1 offspring and F2 fetuses were normal. No deaths or adverse

In an acute toxicity study, oral, intravenous, and subcutaneous doses of taltirelin were compared in Slc:ddY mice, Slc:Wistar rats, and beagle dogs, [276324]. LD50 values were > 5000 mg/kg in mice and rats of both sexes by the oral and subcutaneous routes. In mice, the LD50 value was > 2000 mg/kg by the intravenous route, whereas in rats, it was 799 mg/kg for male and 946 mg/kg for female animals. In dogs of both sexes, minimum lethal doses were > 2000 mg/kg by the oral route. No notable change was seen on autopsy in any animal [276324].

Clinical Development Phase I In a single oral dose study, doses of 10 mg or less of taltirelin led to significantly increased blood pressure, though no change in pulse rate or body temperature was observed [262261]. Headache, abdominal pain, pyrosis, and reduced appetite were the most commonly reported adverse effects [262261]. In a repeated dose study, healthy male volunteers were given 5 mg once a day or 2.5 mg bid, orally, for 14 days. Blood pressure, pulse and body temperature were found to be unchanged, and no laboratory values were significantly different; headache and nausea were the most common side effects observed [262259]. In another phase I study, a food effect was observed [310644]; specifically, plasma concentrations (Cmax and AUC) after a meal were significantly lower than in the fasted state. In a phase I trial in healthy male volunteers, Cmax was reached 3 h after oral administration, and the biological t½ was approximately 2 h [262261]. The plasma concentration of taltirelin rises proportionally with increasing oral doses, although Tmax and t½ are independent of dose [262261]. Taltirelin shows linear pharmacokinetics, with no evidence of accumulation [262259], [262261].

Phase II Taltirelin has been reported to improve scores in the Mini Mental State (MMS) exam in demented patients [241502], to improve slow movements and disorders of range, direction, and rate of movement in patients suffering from various forms of SCD [248816], and to improve ataxic symptoms in

1392 IDrugs 2001 Vol 4 No 12

other studies in patients with SCD [157450], [166359], [176564], [241505]. A study of the effects of taltirelin was performed in 14 patients suffering from various forms of SCD, including olivopontocerebellar atrophy (OPCA), Menzel-type OPCA, late cortical cerebellar atrophy, Machado-Joseph disease, Shy-Drager syndrome, spinopontine degeneration, Friedrich disease, and SCD with slow eye movement [166359]. Escalating doses of taltirelin were given daily for 4 weeks (10 mg/day for week 1, 20 mg/day for week 2, 30 mg/day for week 3, and 40 mg/day for week 4). Clinical ataxic symptoms and other neurological abnormalities were assessed every week, and some improvement was seen, especially in patients with less severe disease [166358]. The effect of taltirelin on the pituitary-thyroid axis in stroke subjects was also investigated [166358]. Subjects were given one dose of taltirelin (2.5 to 20 mg po) daily for 8 weeks, and then blood levels of taltirelin, thyroid hormones and thyrotropin were measured. Plasma levels of taltirelin were elevated with increasing doses. After administration of taltirelin, basal levels of thyroid hormones and TSH had a tendency to increase and decrease, respectively, but those changes remained in the normal range. The secretion of TSH in response to TRH was not significantly affected by taltirelin administration. No significant change in other pituitary hormones was observed after taltirelin administration.

Phase III Long-term (28 to 52 week) placebo-controlled, doubleblind phase III clinical trials have demonstrated drug efficacy, assessed by arrest of disease course and amelioration of ataxia, and safety in the treatment of SCD [310711], [310712]. A multicenter, placebo-controlled, double-blind phase III trial was reported in 1997. The study involved 427 patients with SCD, including 213 in the taltirelin group, 214 in the placebo group. Patients took taltirelin (5 mg bid) or placebo for 28 to 52 weeks. A statistically significant increase in the global improvement rating was observed at the 28th week in the taltirelin group compared to those receiving placebo [310711]. In a crossover study involving 60 patients, taltirelin again showed a statistically significant difference in the global improvement rating [310712].

Side Effects and Contraindications In clinical trials, adverse effects have been mild and infrequent.

Current Opinion Finally, after 30 years of work on TRH [433363] and nearly 20 years since early clinical experiments suggested the utility of the native molecule [261882], taltirelin is the first approved TRH analog with a more practical half-life [382555]. Furthermore, it can be delivered orally. TRH itself has been used quite successfully to treat SCD [433418], [433419], [433420], [433422]. However, the drug has to be injected and its short half-life makes it less than ideal [382555]. Several other TRH analogs have been investigated [244250], [262202], [310641], [310718], [310719], including MK-771 [226125], montirelin [196152], DN-1417 [244254], RX-77368 [217171], azetirelin [215581], and posatirelin [247372]; however, of these, only montirelin appears to be in active development. The data available from many clinical studies evaluating taltirelin for the treatment of SCD [157450], [166359], [176564], [241505], [262259], [262261], [310677], [310680], [310682], [310686], [310689], [310690] [323764], [323766], [323767], [310711], [310712] and dementia [241502] are encouraging and appear to demonstrate its safety and efficacy. Adverse effects seen to date have been mild and infrequent. There are many other conditions in which TRH has been suggested or demonstrated to be useful and an analog with a long half-life opens many possibilities. TRH has been used to treat AD [261882], [262184], [262189], [262192], [262193], [417391], [433388], [433392], [433393], ALS [433377], [433382], [433385], Lennox-Gastaut syndrome [433399], severe childhood epilepsy [433400], and schizophrenia [433401]. Taltirelin and other TRH analogs may be useful in all of these indications. Additionally, taltirelin may be useful in treating alcoholism [310714]. It decreases alcohol consumption in several animal models [237434], [248808], [248819], [280463], [417398]. While, of course, it is necessary to wait for longer term safety data before giving the drug a full stamp of approval, taltirelin appears to be safe and useful in treating SCD. Clinical studies to assess its utility in treating AD are underway.

Development History DEVELOPER Tanabe Seiyaku Co Ltd

OUNTRY Japan

STATUS L

INDICATION Neurodegenerative disease

DATE 18-SEP-00

REFERENCE 382555

Literature classifications Key references relating to the drug are classified according to a set of standard headings to provide a quick guide to the bibliography. These headings are as follows: Chemistry: References which discuss synthesis and structure-activity relationships. Biology: References which disclose aspects of the drug's pharmacology in animal models. Metabolism: References that discuss metabolism, pharmacokinetics and toxicity. Clinical: Reports of clinical phase studies in volunteers providing, where available, data on the following: whether the experiment is placebo-controlled or double- or single-blind; number of patients; dosage.


Chemistry STUDY TYPE Synthesis

RESULT Prepared by methylating 4,5-dihydroorotic acid benzyl ester with methyl iodine, to give a 1methyl derivative which is then debenzylated by hydrogenolysis, using hydrogen over a Pd/C catalyst. The resulting (S)-1-methyl-4,5-dihydroorotic acid is condensed with Lhistidyl-L-prolinamide, using dicyclohexylcarbodiimide and N-hydroxysuccinimide in dimethylformamide.

REFERENCE 35019

Synthesis of other TRH analogs and definition of TRH pharmacophore

Many other TRH analogs have been synthesized and studied in efforts to separate the CNS and endocrine effects of TRH, to increase in vivo stability, and to define the TRH pharmacophore.

262186

Drug detection

Taltirelin can be measured in biological fluids using a radioimmunoassay. The lower limit of detection was 10 pg/ml.

166356

Biology STUDY TYPE In vitro

EFFECT STUDIED Cholinergic effects

EXPERIMENTAL MODEL Central muscarinic cholinergic system

RESULT When applied microiontophoretically to AChsensitive neurons in the rat cerebral cortex, the ACh-induced excitation was potentiated in most neurons tested.

REFERENCE 248823

In vitro

Trophic effects

Cultured ventral spinal cord from Sprague-Dawley rat embryos

Taltirelin had a significant neurite- promoting effect. The effect was more prominent than that of TRH, but not statistically significantly so.

310716

In vivo

Neuronal survival

Axotomy-induced neuronal death in neonatal rats

The left sciatic nerve was transected. Taltirelin was given intraperitonealy for 14 days. Taltirelin prevented the death of motor neurons and preserved motor neuron diameter.

276234

In vivo

Central cholinergic effects

Freely-moving rats

Taltirelin (0.1 to 1 mg/kg ip) caused a marked dose-dependent increase in extracellular ACh and a decrease in choline levels in the hippocampus.

234108

In vivo

CNS effects

Spinal cord injury-induced ataxia in rats

Taltirelin (3 and 10 mg/kg/day for 42 days) promoted recovery from spinal cord injuryinduced ataxia. TRH at 300 mg/kg/day for 42 days had no effect.

148668

In vivo

CNS effects

RMN and rats treated with 3-acetylpyridine (3-AP) and rats with thoracic spinal cord lesions

Both taltirelin (0.3 to 3mg/kg) and TRH (10mg/kg) ameliorated ataxia in 3-AP-treated rats and RMN.

192744

In vivo

CNS effects

Wistar rats treated with 3-AP

Both taltirelin (1 mg/kg) and TRH (10 mg/kg) ameliorated ataxia in 3-AP-treated rats

289284

In vivo

CNS effects

Wistar rats treated with 3AP. Metabolic changes induced were assessed by measuring local cerebral glucose utilization (LCGU).

TRH (10 mg/kg ip) and taltirelin (1 mg/kg ip) partially restored LCGU induced by 3-AP treatment.

417393

In vivo

CNS effects

TRH receptors in rat brain

Following 14 days of treatment, taltirelin caused down-regulation of TRH receptors, but did not affect muscarinic acetylcholine or D2 dopamine receptors.

248818

In vivo

CNS effects

REM sleep and wakefulness in dogs

Taltirelin (0.03 to 0.3 mg/kg iv) and TRH (3 to 10 mg/kg) suppressed entrance into slow wave, deep sleep.

214248

In vivo

Cognitive enhancement

Basal forebrain lesion-, anoxia- or scopolamineinduced memory impairment in rats and mice

In mice (3 to 30 mg/kg) and rats (0.3 to 3 mg/kg), taltirelin improved performance in light-dark box (mice) and shuttle box and Tmaze tests (rats).

35023

1394 IDrugs 2001 Vol 4 No 12

Biology (continued) STUDY TYPE In vivo

EFFECT STUDIED Repeated dose toxicity

EXPERIMENTAL MODEL Dogs

RESULT Taltirelin was administered orally (0.5, 5, 50 mg/kg for 13 weeks and 0.15, 1.5, and 15 mg/kg for 52 weeks). Absorption was dosedependent and did not change during the study. At higher doses, there was a decrease in body weight or a decreased increase. Vomiting, salivation, increased water intake, and hyperlocomotion were also observed.

REFERENCE 276323

In vivo

Repeated dose toxicity

Rats

Taltirelin was administered orally (3, 30, 300 mg/kg/day for 4, 13, and 52 weeks). At higher doses, there was a decrease in body weight. Wet dog shaking, grooming, and hyperlocomotion were also observed.

280581

In vivo

Reproductive toxicity

Pregnant Sprague-Dawley rats

Dams receiving the highest dose (15 mg/kg) exhibited wet dog shaking during gestation. No adverse effect was observed on body weight gain, food consumption, or reproductive performance. F1 offspring and F2 fetuses were normal.

310661

In vivo


Pregnant Japanese white rabbits

No death or adverse effect on food consumption was observed in any dam. Those receiving the highest dose showed rapid breathing and temporarily decreased body weight gain. No adverse effects were observed in the fetuses.

310666

In vivo


Pregnant Wistar rats

No teratogenic effects were observed in the F1 offspring or F2 fetuses. Dams receiving the highest dose (15 mg/kg) exhibited wet dog shaking and hyperlocomotion.

310673

In vivo

Acute toxicity

Oral, iv, and sc doses in Slc:ddY mice, Slc:Wistar rats, and beagle dogs

LD50 values were > 5 g/kg in mice and rats of both sexes, po and sc, and more than 2 g/kg, iv in mice. In rats the LD50 dose, iv, was 799 mg/kg in males and 964 mg/kg in females.

276324

In vivo

Gross behavioral effects

Mice, rats, rabbits, and dogs

Gross behavioral effects were noted in rats and mice at doses of 10- to 100-fold the pharmacological dose. Hyperlocomotion and tail elevation were noted at high doses; salivation, piloerection, tremor and increase respiratory rate were observed. In dogs, increased wakefulness was observed and in rabbits, increased body temperature was noted.

283362

Metabolism STUDY TYPE In vivo

EFFECT STUDIED Pharmacokinetics

MODEL USED Oral and intravenous doses in rats and dogs

RESULT The extent of oral absorption was 9% in rats and 21% in dogs. In both rats and dogs, most of the dose was excreted in the urine within 48 h.

REFERENCE 310739

In vivo

Pharmacokinetics

Oral doses in pregnant rats

The drug was transferred to the fetus in very low amounts (0.002% of the dose per fetus within 3 h in a 19 day pregnant rat) and to the milk of lactating rats (14 days after delivery).

310740

In vivo

Pharmacokinetics

Oral and intravenous doses and injection into the cisterna cerebellomandibularis in rats

Taltirelin was transferred into the brain from cerebrospinal fluid (CSF). Once in the brain, the half-life was approximately 1 h, 8-fold longer than that of TRH.

310741


Clinical EFFECT STUDIED CNS effects

MODEL USED Automated fluctuation analysis of high frequency EEG in 12 patients; performance in the Kana Hiroi (KH; for prefrontal lobe function) and Mini Mental State (MMS; a test for the funtioning of the posterior part of the brain) tests.

RESULT Patients received daily doses of taltirelin (10mg or 20mg). The KH and MMS tests were administered before and after the medication period. Improvements were seen in the MMS score, with some suggestion of dose-dependency. No improvement was seen in the KH scores. Taltirelin appeared to activate subcortical structures, especially A-10.

REFERENCE 241502

CNS effects

Evaluation of cerebellar ataxia, analysis of gait, heel-knee tapping test, finger-nose test, and heel-knee test in 23 patients suffering from SCD and 9 healthy controls.

Oral taltirelin improved slow movements and disorders of range, direction, and the rate of movement.

248816

CNS effects (pituitary-thyroid axis)

23 Patients, 17 with brain thrombosis, 5 with brain hemorrhage, 1 with subarachnoid hemorrhage. Memory impairment was estimated using Hasegawa's memory index.

No significant change was observed in the pituitarythyroid axis following prolonged (8 weeks) oral administration of taltirelin (2.5 to 20mg/day). 39% of patients showed some improvement in their impaired memory. Blood concentrations of up to 8ng/ml were obtained at the 20 mg/day dose.

166358

CNS effects

14 Patients suffering from various types of SCD, specially, 4 cases of olive-ponto-cerebellar atrophy (OPCA), 2 of OPCA (Menzel type), 2 of late cortical cerebellar atrophy, 2 of Joseph disease, 1 of Shy-Drager syndrome, 1 of spinopontine degeneration, 1 of Friedrich disease, and 1 of SCD with slow eye movement.

Escalating doses of taltirelin were given daily for 4 weeks (10 mg/day for the first week, 20mg/day for the second, 30mg/day for the third, and 40mg/day for the fourth). Clinical ataxic symptoms and other neurologic abnormalities were assessed every week. Some improvement was seen, especially in patients with less severe disease.

166359

Phase I trial

Healthy male volunteers

Oral repeated doses (5mg/day or 2.5mg bid) for 14 days caused no change in blood pressure, pulse or body temperature. All laboratory values were normal. Adverse effects were mild (nausea, slight headache). Taltirelin showed linear pharmacokinetics and no accumulation.

262259

Phase I trial

Healthy male volunteers

In a single oral dose study, blood pressure was increased, through pulse and body temperature were unchanged. Plasma concentration increased in proportion to oral dose, Cmax was reached at 3 h and the biological half-life was approximately 2 h; the drug was barely detectable 24 h after a dose.

262261

Phase II trial

11 Patients with SCD and 6 normal controls

Escalating doses of taltirelin were given daily for 4 weeks (10 mg/day for the first week, 20mg/day for the second, 30mg/day for the third, and 40mg/day for the fourth). Clinical ataxic symptoms and other neurologic abnormalities were assessed weekly. Some improvement was seen, especially in patients with less severe disease.

262282

Phase II trial

11 Patients with SCD

Taltirelin (5mg/day) was given for 2 to 8 weeks. Lab values were normal. No patient complained of adverse effects. Ataxia and activity in daily living improved in 9 of the 11 patients.

262283

CNS effects

21 Patients with SCD and 9 normal controls.

Using the heel-knee tapping test, ataxia was improved.

262279

CNS effects

3 Patients with SCD

3 h after oral administration of taltirelin (20 mg), ataxic symptoms were significantly improved.

310686

CNS effects

16 Patients with SCD

Patients took taltirelin (5 mg/day) for 4 to 14 weeks. Significant improvements were seen in orthostatic symptoms, dysbasia, and in daily living activities. No adverse effects or abnormal lab values were reported.

310689

CNS effects

Phase I trial in healthy volunteers.

Improvements were reported in the latent heel-knee tapping test, as assessed using a motion measurement system.

310644

1396 IDrugs 2001 Vol 4 No 12

Clinical (continued) EFFECT STUDIED Metabolism

MODEL USED Phase III trial in 427 patients with SCD; 213 received taltirelin (5 mg), 214 received placebo.

RESULT Levels of neurotransmitters and their metabolites were determined in CSF. Results suggested that taltirelin might enhance noradrenaline turnover in the CNS.

REFERENCE 310711

Global improvement rating.

Phase III trial in 60 patients with SCD.

Patients received taltirelin (5 mg/day) for 4 to 14 weeks. Significant improvements were observed in orthostatic symptoms, dysbasia, and in daily living activities. No adverse effects or abnormal lab values were reported. S

310712

Associated patent Title Antiepileptic composition. Assignee Takeda Chemical Industries Ltd, Japan Publication DE-03234061 24-MAR-83 Priority JP-1981-146946 16-SEP-81 Inventors Inanaga K, Nagawa Y.

Associated references •• •

of outstanding interest of special interest

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1398 IDrugs 2001 Vol 4 No 12

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310740 Disposition of taltirelin. (2): the transfers into the fetus and milk, sex-related difference after single oral dose administration and blood concentration after repeated oral dosing in rats. Hirohiko K, Akiko K, Juko S, Masayoshi Y XENOBIOT METAB DISPOS 1997 12 5 475 - 482

310666 Reproductive and developmental toxicity studies of taltirelin hydrate (3): perinatal and postnatal study in rabbits by oral administration. Imahie H, Nishida A, Imado N, Asano Y J TOXICOL SCI 1997 22 Suppl 2 395 - 403

310741 Disposition of taltirelin. (3): the transfer into the brain and brain distribution in rats. Hirohiko K, Takeshi F, Susumo C, Juko S, Masayoshi Y XENOBIOT METAB DISPOS 1997 12 5 483 – 490

310673 Reproductive and developmental toxicity studies of taltirelin hydrate (2): teratogenicity study in rats by oral administration. Imahie H, Kobayashi T, Nishida A, Imado N, Asano Y J TOXICOL SCI 1997 22 Suppl 2 381 - 394 310675 Reproductive and developmental toxicity studies of taltirelin hydrate (1): fertility study in rats by oral administration. Imahie H, Kobayashi T, Imado N, Inui T, Ariyuki F, Asano Y J TOXICOL SCI 1997 22 Suppl 2 371 - 379 310677 Efficacy of the TRH derivative and TA-0910 on spinocerebellar degeneration. Teruhiko K, Yuichi T, Takako Y SHINRYO SHIN'YAKU 1997 34 7 701 – 710 310680 Endocrinologic evaluation of oral TRH derivative (TA-0910) for spino-cerebellar degeneration. Tadanori Y, Motomori I, Shigenobu N, Mitsuhiro T CLIN ENDOCRINOL 1997 45 8 805 - 810 310682 Examination of the effectiveness and safety of TA-0910 for an ataxia state of olivopontocerebellar atrophy. Examination using quantitative evaluation. Tokio S SHINRYO SHIN'YAKU 1997 34 5 539 - 546

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433388 A peptide enhancement strategy in Alzheimer's disease: pilot study with TRH-physostigmine infusions. Mellow AM, Aronson SM, Giordani B, Berent S BIOL PSYCHIATRY 1993 34 271 - 273 433390 Regulatory peptides as a source of new drugs-the clinical prospects for analogs of TRH which are resistant to metabolic degradation. Metcalf G BRAIN RES REV 1982 4 389 - 408 433392 The effects of TRH and scopolamine in Alzheimer's disease and normal volunteers. Molchan SE, Mellow AM, Hill JL, Weingartner H, MArtinez R, Vitiello B, Sunderland T J PSYCHOPHARMACOL 1992 6 489 – 500 433393 Scopolamine effects on the pressor response to thyrotropinreleasing hormone in humans. Molchan SE, Hill JL, Minichiello M, Vitiello B, Sunderland T LIFE SCI 1994 54 933 - 938 433394 On the neuropharmacology of thyrotropin-releasing hormone (TRH). Yarbrough GG PROG NEUROBIOL 1979 12 291 - 312 433396 Structural and functional organisation of the gene encoding the human thyrotropin-releasing hormone receptor. Matre V, Hovring PI, Orstavik S, Frengen E, Rian E, Velickovic Z, Murray-McIntosh RP, Gautvik KM J NEUROCHEM 1999 72 40 - 50 433397 Limbic, hypothalamic, cortical and spinal regions are enriched in receptors for thyrotropin-releasing hormone: evidence from [3H]ultrofilm autoradiography and correlation with central effects of the tripeptide in rat brain. Sharif NA, Burt DR NEUROSCI LETT 1985 60 337 - 342 433398 Increases in thyrotropin-releasing hormone messenger RNA expression induced by a model of human temporal lobe epilepsy: effect of partial and complete kindling. Knoblach SM, Kubek MJ NEUROSCIENCE 1997 76 85 - 97

433364 Thyrotropin-releasing hormone (TRH) precursor processing. Characterization of mature TRH and non-TRH peptides synthesized by transfected mammalian cells. Sevarino KA, Goodman RH, Spiess J, Jackson IM, Wu P J BIOL CHEM 1989 264 21529 - 21535

433399 Clinical effects of TRH analog (DN-1417) on the Lennox syndrome. Ueda S, Nakamura J, Inanaga K J JPN EPILEPSY SOC 1983 1 31 - 39

433365 Thyrotropin-releasing hormone: regional distribution in rat brain. Winokur A, Utiger RD SCIENCE 1974 185 265 - 267

433400 Clinical effects of thyrotropin-releasing hormone for severe epilepsy in children: a comparative study with ACTH therapy. Matsumoto A, Kumagi T, Takeuchi T, Miyazaki S, Watanabe K EPILEPSIA 1987 28 49 55

433366 Controversies in TRH biosynthesis and strategies towards the identification of a TRH precursor. Jackson IMD ANN N Y ACAD SCI 1989 553 7 - 13 433368 Characterization and expression of the gene encoding rat thyrotropin-releasing hormone (TRH). Lee SL, Sevarino K, Roos BA, Goodman RH ANN N Y ACAD SCI 1989 553 14 - 28 433370 Biosynthesis and secretion of TRH in the rat pancreas. Giraud P, Dutour A, Quafik L'H, Salers P, Kowalski C, Maltese JY, Lissitzky JC, Renard M, Oliver C ANN N Y ACAD SCI 1989 553 479 - 482 433373 C-terminal amidation of neuropeptides. Gly-Lys-Arg extension as efficient precursor of C-terminal amide. Gomes S, di Bello C, Hung LT, Genet R, Morgat J-L, Fromageot P, Cohen P FEBS LETT 1984 167 160 - 164 433374 Immunocytochemical distribution in rat brain of putative peptides derived from thyrotropin-releasing hormone prohormone. Lechan RM, Wu P, Jackson IM ENDOCRINOLOGY 1987 121 1879 - 1891

433401 Neuropeptide therapies in chronic schizophrenia: TRH and vasopressin administration. Brambilla F, Aguglia E, Massironi R, Maggioni M, Grillo W, Castiglioni R, Catalano M, Drago F NEUROPSYCHOBIOLOGY 1986 15 114 - 121 433402 Metabolism and excretion of exogenous thyrotropin-releasing hormone in humans. Bassiri RM, Utiger RD J CLIN INVEST 1973 52 1616 1619 433403 Studies on the inactivation of thyrotropin-releasing hormone. Redding TW, Schally AV PROC SOC EXP BIOL MED 1969 131 415 - 420 433404 Comparative metabolism and conformation of TRH and its analogs. Griffiths EC, Kelly JA, Ashcroft A, Ward DJ, Robson B ANN N Y ACAD SCI 1989 553 217 - 231 433405 TRH degradation rates vary widely between different animal species. Brewster D, Waltham K BIOCHEM PHARMACOL 1981 30 619 - 622

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433407 Neurobiology of cyclo(His-Pro). Prasad C ANN N Y ACAD SCI 1989 553 232 - 251 433408 Application of the primary hydration shell approach to locally enhanced sampling simulated annealing: computer simulation of thyrotropin-releasing hormone in water. Rosenhouse-Dantsker A, Osman R BIOPHYS J 2000 79 66 - 79 433410 Two conformations of TRH in solution. Vicar J, Abillon E, Toma F, Piriou F, Lintner K, Blaha K, Fromageot P, Fermandjian S FEBS LETT 1979 97 275 - 278 433411 Molecular cloning of a functional human thyrotropin-releasing hormone receptor. Matre V, Karlsen HE, Wright MS, Lundell I, Fjeldheim AK, Gabrielsen OS, Larhammar D, Gautvik KM BIOCHEM BIOPHYS RES COMMUN 1993 195 179 - 185 433414 In vitro biochemical characterization and autoradiographic distribution of 3 H-thyrotropin-releasing hormone binding sites in rat brain sections. Rostene WH, Morgat JL, Dussaillant M, Rainbow TC, Sarrieau A, Vial M, Rosselin G NEUROENDOCRINOLOGY 1984 39 81 86 433415 Autoradiographic localization of thyrotropin-releasing hormone receptors in the rat central nervous system. Manaker S, Winokur A, Rostene WH, Rainbow TC J NEUROSCI 1985 5 167 - 174 433418 Branched-chain amino acid therapy for spinocerebellar degeneration: a pilot clinical crossover trial. Mori N, Adachi Y, Takeshima T, Kashiwaya Y, Okada A, Nakashima K INTERN MED 1999 38 401 - 406

433419 Efficacy of TRH-T for spinocerebellar degeneration-the relation between clinical features and effect of TRH therapy. Waragai M, Ogawara K, Takaya Y, Hayashi M RINSHO SHINKEIGAKU 1997 37 587 - 594 433420 Effect of thyrotropin-releasing hormone (TRH) on cerebral blood flow in spinocerebellar degeneration and cerebrovascular disease. Izumi Y, Fukuuchi Y, Ishihara N, Imai A, Komatsumoto S TOKAI J EXP CLIN MED 1995 20 203 - 208 433422 Clinical manifestations and thyrotropin releasing hormone therapy in cerebellar degenerations. Wang HC, Chiu HC CHUNG HUA I HSUEH TSA CHIH 1991 47 161 - 168 433424 Isolation and characterization of human thyrotropin-releasing hormone (TRH) from an endocrine pancreatic tumor. Vuolteenaho O, Leppaluoto J, Ying SY, Samaan NA REGUL PEPT 1990 31 33 - 40 433425 Central hypothyroidism due to isolated TRH deficiency in a depressive man. Mori M, Shoda Y, Yamada M, Murakami M, Iriuchijim T, Ohshima K, Kobayashi I, Kobayashi S J INTERN MED 1991 229 285 - 288 433426 Hypothalamic hypothyroidism due to isolated thyrotropinreleasing hormone (TRH) deficiency. Katakami H, Kato Y, Inada M, Imura H J ENDOCRINOL INVEST 1984 7 231 - 233 433496 Anticonvulsant effect of DN-1417, a derivative of thyrotropinreleasing hormone and liposome-entrapped DN-1417, on amygdaloidkindled rats. Mori N et al EPILEPSIA 1992 33 6 994 433991 Tanabe Seiyaku. Barker S, Hatakenaka UBS WARBURG (JAPAN) 2001 September 19.