DE4004549A1 - Use of glutamic acid or derivs. for treating hypertension - by oral admin., effective for patients not responding to other treatments - Google Patents

Abstract

The use of glutamic acid (I) or related amino acids, or their derivs., metabolites or salts, for the oral treatment of hypertension is claimed. The dose is up to 30 g or more per day, esp. 3 4g doses initially and the 3 2g doses for maintenance. If required, (I) is administered together with a saliuretic, other antihypertensives or Mg, and provides blood pressure readings of 140 +/- 25 mm systolic and 70 +/- 20 mm diastolic. USE/ADVANTAGE - Since intravenous admin. of (I) is known to increase the blood level of adrenaline and other vasoconstrictors its use in hypertensive patients has been contraindicated. It is now found, however, that oral admin. of (I) reduces blood pressure, even in patients who do not respond to conventional treatments. (I) can cause mild sleep disturbance but this wears off after a week and in no cases has it been severe enough to cause the treatment to be discontinued.

Description

The invention relates to a new indication of Glutamic acid, Glutaminsäurederivaten, Glutaminsäureab and glutamic acid salts and glutamic acid related amino acids and their derivatives, derivatives and salts.

According to Malherb (H. Weil Malherb, Lecture on the conference Dt Ges Ges Neurologie, Hamburg 1952. Quoted after Kohl, H .: Amino acids, Editio Cantor KG, Aulendorf, 1954), the intravenous administration of glutamic acid and its related substances to an adrenaline rise in blood. The anatomical and physiological delimitation of the auto-nomen nervous system at the end of the 19th century provided the background for the work of Dale, et al. (Dale HH: On some physiological actions of ergot. J. Physiol. (London) 34: 163, 1906. Cited after H. Lydin and G. Loh müller: β -Receptor Blocker, Edition Springer-Verlag: Herzkrankheiten, Hsgb .: H Roskamm, H. Reindell, second edition, 753-776, 1982). According to Lydin and Lohmüller, epinephrine has a vasoconstrictory effect under physiological conditions, ie an increase in blood pressure. From the work of Malherb, the contraindication for the treatment of hypertension with glutamic acid, glutamine derivatives, glutamic acid derivatives and their salts has been derived so far.

Recent publications by Garthwaite et al (Garthwaite, J. et al Nature 336, 385-388; 1988. Barbour B. et al. Nature 335, 433-435; 1988. Stevens, C.F., Nature 322, 210-211; 1986. Vanhoutte, P.M. Nature 327, 459-460; 1987. Stevens, C.F., Nature 336, 308-309; 1988) showed that glutamine acid and its derivatives or salts by synthesis of a EDRF (Endothelium Derived Releasing Factor and Endothelin, the strongest vasoconstrictor) in the regulation of blood pressure are involved.

According to the invention, however, has been found that the oral Ingestion of glutamic acid, glutamic acid derivatives, gluta Minic acid derivatives, glutamic acid salts and the Glutamic acid related amino acids and their derivatives, Offspring and salts contrary to the previous view a treatment of hypertension allows.  

According to the invention, endothelial cells have been recognized Na / K dependent amino acid carrier possessing i.a. Glu tamic acid and its derivatives or salts in substrate con Carrying form transported into the cells and that the Glutamic acid or its derivatives and salts both at the Synthesis of EDRF as well as of endothelin significantly be are involved. As the glutamic acid and its derivatives i.a. also act as neurotransmitters in the CNS, it may e.g. with adequate neurophysiological or neuropsychologi burden and inadequate physiological offer Glutamic acid or Glutaminsäurederivaten to a Depletion of cells on glutamic acid and its derivatives come so that the blood pressure control mechanism from his physiological balance device. Under hypertensive Conditions it comes to a difficult expression of the Aminoaäurecarriers.

According to the invention has further been found that there is a Defect of the synthetases of EDRF and endothelin. Of crucial importance is the enterohepatic Circulatory system via transaminirung plus dehydrating Deamination or alternatively by transamination, Ami dehydrogenation plus hydrolytic deamination or by direct eliminating deamination of nitrogen forms (Jungermann, Möhler, 1980), which then in the Endo thelzellen by hydrolysis and oxidation in stick substance monoxide or dioxide is converted, the actual Relaxation factor (own results). The reason why the administration of other amino acids did not cause significant blood leads, that these amino acids to Gluta min and alanine are rebuilt, then directly or indi excreted as urea via the kidney, or in the starvation phase for gluconeogenesis to be used the (Jungermann, Möhler, 1980).  

The reason why the adrenalin observed by Malherb Increase in blood level with intravenous administration of Glutamic acid does not matter is in the alpha and To see the effects of adrenalin.

On the basis of these facts could by Administration of adequate glutamic acid or derivative amounts per os found a new antihypertensive therapy who because, despite exhausting all therapeutic Possibilities of modern outpatient antihypertensive therapy Pie are 25% of all hypertensives from the above Reasons for conventional antihypertensive therapy resistant to therapy.

According to the invention results in patients who konven at treatment of treatment-resistant hypertensives are, when treated with L-glutamic acid per os following: A strict therapy protocol was set up: same constant RR control of the patient twice a day, long same compensation of the previous medication in Dreita rhythm, medical supervision of the patient in one week frequent distance; Laboratory control of electrolytes (Well, K, Ca, Cl), as changes in the electrolyte homeostasis too possibly cytotoxic changes in concentration of ex lead to glutamates. The of the patients initially described light sleep disorders ver disappeared after 1 week and under no circumstances forced to Discontinuation of therapy.

Examples

Dosage range: from 0.33 g to 30 g and more per day.  

Best results are achieved with the following dosage: initial 7 days 3 × 4 g, maintenance dose 3 × 2 g, at high exercise load increase dose until normal otone RR values are reached. Additionally, if necessary Saluretics, other antihypertensives and magnesium. With At this dosage, the blood pressure values are systolic 140 ± 25 mm Hg and diastolic at 70 ± 20 mm Hg.

The patients find it very pleasant that the usual tiredness does not occur. observation period 3 months.

Selection of six patients F.H. before glutamic acid therapy 140/100 under Adalat SL 140/90 glutamic acid B. A. before 150/110 beta blocker 130/70 under glutamic acid L. E. before 145/110 Nifedipine and / or Prelis mite 125/80 glutamic acid with saluretic acid; after discontinuation of saluretic renewed RR increase now trial with additional magnesium B. H. before 160/90 no therapy 140/80 under glutamic acid S.A. 140/110 no therapy 140/90 glutamic acid J.M. 170/110 Salad salad 140/80 under glutamic acid

Mean ± 20 mm Hg syst. 10 mm Hg diast.

Another 30 patients had before treatment or under con of conventional antihypertensive therapy medium blood pressure values of systolic of 180 1 + 0 30 mm Hg and diasto 100 1 + 0 20 mm Hg.

Table II

RR values of 30 patients before antihypertensive treatment

Table III

RR values of 30 patients after antihypertensive treatment

The above is the usual measured blood pressure specified.

Claims (3)

1. Use of glutamic acid, glutamic acid derivatives, Glutaminsäureabkömmlingen, Glutaminsäuresalzen and the Glutamic acid related amino acids and their derivatives, Progeny and salts per os to the previously contraindicated Treatment of hypertension. 2. Use of glutamic acid, glutamic acid derivatives, Glutaminsäureabkömmlingen, Glutaminsäuresalzen and the Glutamic acid related amino acids and their derivatives, Progeny and salts per os in a dosage of up to 30 g and more per day for the treatment of hypertension. 3. Use of glutamic acid, glutamic acid derivatives, Glutaminsäureabkömmlingen, Glutaminsäuresalzen and the Glutamic acid related amino acids and their derivatives, Progeny and salts in a dosage of 3 x 4 g per Day per os for the initial treatment of hypertension and in a dosage of 3 × 2 g per day per os as Erhal tung dose.