DE19953625A1 - Use of 5HT-1A serotonin receptor agonists for the treatment of genetic or functional respiratory rhythm disorders - Google Patents

Abstract

The invention relates to the use of 5HT-1A-serotonine agonists or a pharmaceutically compatible salt or ester thereof for the therapy or prophylaxis of disturbances of central rhythmogenesis in the respiratory system.

Description

This invention relates to the use of a 5HT-1A serotonin agonist or a pharmaceutically acceptable salt or ester thereof for therapy or Prevention of disorders of the central rhythmogenesis of breathing.

The respiratory center was described by Smith et al., Science 254, (1991), 1726-729, below Brainstem, the so-called Pre-Bötzinger complex localized. How it works this center is controlled by coupled neuron groups that interact chemically-synaptically (Richter et al., Current Opinion in Neurobiology 2, 1992, 788-793). The question of the origin of the network drive is still unsettled.

Of particular note are those to be treated according to the invention Respiratory arrhythmias primary respiratory arrhythmias, d. H. Developmental disorders of the CNS, in which respiratory rhythm disorders occur, e.g. B. with RETT syndrome, which is genetic, with developmental disorders or Degenerations of the CNS, in which respiratory rhythm disorders occur, e.g. B. at the Olivo-ponto-cerebellar atrophy, if glycergic inhibition fails, for example in the case of a genetic disease of the hyperecplexia type and in Premature or newborns with long apnea phases for the prophylaxis of a sudden Child deaths (Sudden Infant Death Syndrome = SIDS).

In the secondary respiratory rhythm disturbances according to the invention are particularly to mention those with overdose of barbiturates (also anesthetic, sleeping pills) or in case of overdose of opiates respiratory arrests such as,

This variety of respiratory arrhythmias was available with the previously difficult to treat or prevent standing therapeutic agents.

The 5HT-1A receptor subform is widely used in the CNS, v. a. in hypocampus, Septum and amygdala, in areas which are believed to be associated with the Control of mood related.

Respiratory center neurons predominantly express the 5HT-1 A- Receptor type, but also the 5HT-2 receptor type, not or hardly the 5HT-3 Receptor type.

Known serotonin 1A receptor agonists include a. 8-hydroxy-2- dipropylaminotetralin (8-OH-DTAT), 8- {4- (2-pyrimidinyl) -1-piperazinyl [butyl} -8- azaspirol] 4,5,) decan-7,9-dione (buspirone), 5-carboxamidotryptamine (dipropyl-5CT), R (+) - 5-fluoro-8-hydroxy-2-dipropylaminotetralin (R (+) - UH-301), 2- (2,6- Dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane (WP-4101), Gepiron, Ipsapiron, MDL 72832 and RU 24969, of which Buspiron is particularly preferred.

Of these, v. a. 8-Hydroxydipropylaminotetralin absolute selectivity for the 5HT-1 A receptor, while the non-benzodiazepine anxiolytics Buspirone and Gepiron and other ligands, such as MDL 72832, are partial agonists.

So far, the serotonin receptor agonists according to the invention as v. a. Anxiety drugs (anxiolytics) are used taking advantage of its lack of sedative and breathing depressive effect.

Among others, Smoller et al., Am I. Resp. Critical Care Med. 154, (1996), 6-17, describe buspirone as an effective medication to treat panic and / or Anxiety in patients with respiratory disorders, d. H. as an anxiolytic Shortness of breath and dyspnea as a result of airway obstruction.

Mendelson, Am. Rev. Resp. Dis. 141, (1990), 1527-1530, describes the positive ones Effects of buspirone as respiratory stimulant, which also has an effect in sleep not lose.  

Argyropoulu, Respiration 60, (1993), 216-220, describes a connection between Buspiron and the breath control and proposes Buspiron as Therapeutic agent of dyspnea in patients with chronic lung diseases before.

It follows that buspirone itself does not have a breathing depressive effect like a Most of the anxiety drugs like barbiturates and benzodiazepines but one has a breath-stimulating effect, see also Garner et al. At the. Rev. Resp. Dis. 13914 (1989) 946-50.

In the publication Wilken et al. J. Pediatr. 130, (1997), 89-94, is under discussion the use of 5-HT-1A receptor agonists in apneuistic Respiratory rhythm disorders discussed.

It is listed that the inspiratory activity is usually in the respiratory center through the so-called lung expansion reflex (or according to the first descriptors also Herring-Breuer reflex called) is ended. The sensitive afference signals that the Triggering reflex come from the so-called lung stretch receptors in the walls of the bronchial tree. These afferents in the vagus nerve are first observed in the lower brainstem (ventrolateral nucleus of the solitarius tract) and then run to areas in the Pons (Nucl. parabrachialis and Nucl. Kölliker- Fuse). After they are switched again there, the efferents move Pathways of reflex to the caudal center of respiration and inhibit them there Volley discharge of inspiratory nerve cells.

That means a direct mechanical lesion or one due to Poor circulation failure of these cranial areas in the pons turn off the lung stretch reflex. The result is an apneustic Extension of inspiration.

From this publication it can be seen that mechanical destruction or failures caused by local poor blood circulation / cerebrovascular insults of these pontine areas lead to and by apneustic arrhythmia Buspirone can be treated.

Surprisingly, it has now been found that the serotonin receptor Agonists not only by mechanical destruction or by local ones  Reduced blood flow / cerebrovascular insults triggered apneustic Respiratory rhythm disturbances can be treated, but also those caused by Genetic or functional disorders of a completely different kind occur that the Do not directly involve lung stretch reflex.

According to the invention, the following indication areas are preferred.

• 1. RETT syndrome, a developmental disorder (genetic), which is diagnosed primarily in girls aged 6-18 months and occurs with a frequency of 1: 10,000.
  In the progression disorders of motor skills, speech and breathing occur. It is believed that the respiratory rhythm disorder is due to a malfunction of the synaptic interaction in the respiratory network. Glutamatergic, but also inhibitory and seratergic processes are presumably involved.
• 2. Developmental disorders, hypoplasia and degenerative diseases in the area of the brain stem, ie developmental disorders that affect the brain stem, among other things, and hypoplasia or degeneration in the area of the brain stem z. B. the type of olivo-ponto-cerebellar atrophy.
  Olivo-ponto-cerebellar atrophy (OPCA) is a degenerative disease that occurs primarily in adulthood. A similar complex of symptoms can also occur in young children as a developmental disorder.
  The areas of the pon, the locus coerulus and the upper parts of the brain stem, which are important for nervous respiratory regulation, are affected. Respiratory rhythm disturbances can occur during the progression of the OPCA syndrome.
• 3. Developmental disorders of glycine receptors for synaptic inhibition a genetic failure of glycine inhibition, which leads to Disease pattern of hyperkplexia leads. By the relative loss of everyone Glycinerergic inhibition occurs during postnatal development clinical symptom of an increased fright and nervous disorder Regulation of motor skills, which leads to the term hyperecplexy, and also to  a disturbance in the central rhythmogenesis of breathing and the regulation of pharyngo-laryngeal motor skills.
• 4. For the prevention of Sudden Infant Death (SIDS) in infants with frequent and long periods of sleep apnea.
  It is believed that the cause of death in sudden infant death is a terminal hypoxic depression of ventilation due to the blockage of the synaptic interaction in the respiratory center and ultimately leads to a collapse of the cardio-respiratory regulation.
• 5. Use for therapy and prophylaxis of barbiturates or Opiate overdose and drug abuse Respiratory rhythm disorders and for prophylaxis with any anesthesia, furthermore also with respiratory rhythm disorders in the event of failure of the glutamatergenic synaptic Processes (NMDA receptor blockade), e.g. B. in epilepsy and Pain therapy.

According to the invention, a significant improvement in spontaneous breathing was found in a female RETT syndrome patient under therapy with 3 × 2 mg buspirone orally in control polysomnography. The frequency of the apneusis states had dropped significantly and their severity was significantly reduced. The arterial saturation values of O _{2 also} decreased only minimally to 91%, cf. previously 55%, from.

An influence on the rest of the treatment or significant side effects could not be observed.

When treating a male patient suffering from hypoplasia from Cerebellum, Pons and Ncl. olivaris, under therapy with 2 × 2 mg, buspirone oral, also an impressive reduction in apneusis states and its Consequences can be brought about. In particular, there was no need for Bag ventilation more. The frequency of the apneus attacks could be from 60 Conditions can be reduced to 3-5 a day, also reducing the intensity has been.  

Thus, the invention provides 5HT-1A receptor agonists as a drug for the first time Treatment and prophylaxis of genetic and functional primary and secondary respiratory rhythm disorders are available as well as an additional drug Anesthetics.

The 5HT-1A receptor agonists mentioned above can, as in the Known pharmaceutical practice, with the usual excipients to drug forms oral, parenteral, intracerebral, rectal or intranasal application be formulated.

As is self-evident for the expert, the individual dosage of the individual active substances according to the invention from several factors, such as. B. the Type and severity of the disease, the individual response of the patient who Concomitant medication, the age or weight of the patient.

Claims (19)

1. Use of a 5HT-1A agonist or a pharmaceutical compatible salt thereof, for therapy or genetic or functional respiratory arrhythmia. 2. Use according to claim 1, wherein the disturbances of the central Rhythmogenesis due to blockage of inhibitory interneurons or by them controlled processes. 3. Use according to claim 1 or 2, wherein the disturbance of the central Rhythmogenesis due to developmental disorders and / or degeneration in the Area of the brainstem. 4. Use according to claim 2 for anesthesia as additional medication, Barbiturate overdose, abuse, opiate overdose, or abuse. 5. Use according to claim 2 or 3 in hypoxia / ischemia of the brain stem in acute or chronic hypoxia / ischemia (sleep apnea, Pickwick Syndrome) and cerebral circulatory disorder. 6. Use according to claim 2 or 3 for the prophylaxis of sudden infant death Syndrome (SIDS). 7. Use according to claim 2 or 3 in the treatment of Respiratory rhythm disorders in the event of failure of synaptic glutamatergic Processes during treatment with NMDA blockers. 8. Use according to claim 3 in the treatment of respiratory rhythm disorders in RETT syndrome. 9. Use according to claim 3 in respiratory rhythm disorders caused by Developmental disorders that affect the brain stem.   10. Use according to any one of claims 1 to 9, wherein the 5HT-1A agonist Buspirone or a pharmaceutically acceptable salt thereof. 11. Use according to one of claims 1 to 9, wherein the 5HT-1A agonist 8- Hydroxy-2-dipropylaminotetralin (8-OH-DPAT) or a pharmaceutical tolerable salt of it. 12. Use according to any one of claims 1 to 9, wherein the 5HT-1A agonist 5- Carboxamidotryptamine (Dipropyl-5CT) or a pharmaceutically acceptable one Salt of it is. 13. Use according to any one of claims 1 to 9, wherein the 5HT-1A agonist R (+) - 5-fluoro-8-hydroxy-2-dipropylaminotetralin (R (+) - UH-301) or a pharmaceutically acceptable salt thereof. 14. Use according to one of claims 1 to 9, wherein the 5HT-1A agonist 2- (2,6-Dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane (WP-4101) or is a pharmaceutically acceptable salt thereof. 15. Use according to any one of claims 1 to 9, wherein the 5HT-1A agonist Gepiron or a pharmaceutically acceptable salt thereof. 16. Use according to any one of claims 1 to 9, wherein the 5HT-1A agonist Ipsapirone or a pharmaceutically acceptable salt thereof. 17. Use according to any one of claims 1 to 9, wherein the 5HT-1A agonist MDL 72832 or a pharmaceutically acceptable salt thereof. 18. Use according to any one of claims 1 to 9, wherein the 5HT-1A receptor Agonist RU 24969 or a pharmaceutically acceptable salt thereof. 19. Use according to any one of claims 1 to 9, wherein the 5HT-1A receptor Agonist BAYR 1531 or a pharmaceutically acceptable salt thereof.