Use of ammonium compounds and/or urea

Details Use of ammonium compounds and/or urea Use of ammonium compounds and/or urea

1998-09-02

2001-12-25

Pak, John (Department: 1616)

Drug, bio-affecting and body treating compositions

Inorganic active ingredient containing

Ammonia or ammonium compound containing

C424S439000, C424S719000, C426S801000, C514S588000, C514S740000

Reexamination Certificate

active

06333055

ABSTRACT:

This application is a 371 of PCT/SE97/00361, filed on Mar. 4, 1997.
The present invention relates to the new use of physiologically innocuous ammonium compounds and/or urea, an infant formula or a pap and a method for the prevention or prophylaxis of cot death.
The phenomenom called “cot death” or “Sudden Infant Death Syndrome” (SIDS) has heretofore not been given any satisfactory explanation.
The syndrome affects apparently previously healthy children at the age of about 3 to 5 months, which in most cases are found dead under sleep by their parents. As far as I know hardly any cases of SIDS have been reported, wherein death has suddenly occurred in a child which has been regarded as awake. On the contrary a general pattern seems to be that the child has fallen asleep and is sleeping very peacefully after having been normally awake and in certain cases even having been sensorically comparatively well stimulated before falling asleep. Any signs of hypoxia (cyanosis) have as a rule never been observed before death. In certain cases, however, it has been asserted that autopsy findings have shown signs of chronical hypoxia [Hunt C E, Clin Perinatol, 19, 757-771 (1992)]. Furthermore, it has sometimes been asserted that insufficient breathing has been observed clinically on some children and sometimes also on brothers and sisters to children which have died from SIDS. Lately parents to children at an age of less than 6 months have been recommended to have the child sleeping on its back because it has appeared that this recommendation, when complied with, has resulted in a lower incidence of SIDS. Recently results have been published which indicate that supine position in the bed should be the position in which a high ambient temperature is best tolerated. [Ponsonby A-L et al, N Engl J Med, 329, 377-382 (1993)].
The present invention emanates from a new hypothesis about the cause of SIDS based on certain observations made and earlier published theories for the metabolism of mammals.
In order that an animal or a human being should be able to live it is required that its body functions are regulated in such a way that there is an acid-base balance. Expressed in another way: A normal pH-value must exist in the cells, in the extracellular liquid and in the cell organelles. If this is not the case first slight functional disorders, then even increasing diseases and finally death of structures, cells and the whole organism occurs. For instance, it is known that the mortality in several diseases increases when the pH value of the extracellular liquid (normally 7.40) is above 7.55 or below 7.20.
Under the latest decades the opinion of the acid-base balance has not changed materially. During the 1980's, however, Atkinson and co-workers [Atkinson D E et al, Curr Top Cell Regul, 21, 261-302 (1982)] again called attention to the previously known, but among physiologists and medical physicians not accepted fact that the metabolism of mammals not only produced the main metabolites carbon dioxide, water and urea but also hydrogen carbonate. His theory also meant that the metabolism by producing hydrogen carbonate above all via amino acid metabolism in order to result in the metabolic end products carbon dioxide and water must be supplied with protons and that this process for quantitative reasons had to occur via the ornithine cycle. One of the objections against this theory has been that if such an important life process does not function the animal or the human being in question should rapidly die. However, no such lacking function of the system proposed by Atkinson has ever been pointed out and even less been proven which constitutes one of the deficiencies of his theory.
The hypothesis that the above-mentioned acid-base system at a possible malfunction might cause the part of SIDS which can be explained with a respiratory insuffiency has now been made the basis of the present invention.
The fundamental principle of the hypothesis above is that deficient protonizing of endogenously produced hydrogen carbonate rapidly, according to Atkinson, results in a progressive alkalizing which as known about this condition may lead to progressive hypoventilation, i.e. insufficient breathing. An increase in the concentration of hydrogen carbonate is certainly counteracted by a compensatory increase in PCO
2
which is one of the physiological results of a hypoventilation.
The other consequence of the hypoventilation is one of a relative hypoxemia (not particularly pronounced low arterial oxygen gas saturation of haemoglobin due to a normally left-displaced saturation curve for oxygen in small children) and later a secondary lactic acidosis (lactic acid acidosis). This will thus in combination lead to a raise in the pH-value to a metabolic alkalosis which finally only partially is compensated by a hypercapnia just as the lactic acid acidosis already mentioned. The cumulation of hydrogen carbonate and the alkalosis caused thereby hence dominates this process. The metabolic alkalosis which hence is only partially compensated, enhances still more the Hb dissociation curve for fetal haemoglobin which is already displaced to the left. Added to this effect upon the O
2
dissociation curve will be the influence that a possible increase in body temperature exerts on PCO
2
, which accordingly increases and as a consequence thereof contributes to a progressive respiratory depression. The result will be an increasing and finally massive metabolic alkalosis which leads to further respiratory depression, hypercapnia and hypoxia, particularly in peripheral tissues, in spite of a relatively good arterial oxygen gas saturation and accordingly absence of cyanosis. Finally, the respiratory centre cannot function normally due to the progressive acid-base displacement and the hypoxia but during sleep, which often is combined with a child which is too warm (a high temperature increases PCO
2
), a still more serious hypoxia appears as a consequence of the fact that the hypoxic respiration drive does not function in such small children. The end result will be a death which by physicians is given the diagnosis SIDS.
The deficient protonization of the hydrogen carbonate ions of the child might be an effect of a deficient supply of ammonium ions in the liver which in turn might be due to the lack of natural content of urea in the infant formulas or to the fact that the rich supply of urea in the mother's milk (often twice as much as in the mother's plasma) is not metabolized in the normal way to ammonium ions. This decomposition of urea usually occurs in the gastrointestinal tract by urease-producing bacteria which gradually colonize the initially sterile intestine of the neonate. The bacterial colonization normally occurs during the first weeks of life but might according to the present hypothesis have been delayed, inhibited, or be insufficient in another way in the children which experience a respiratory insufficiency resulting in SIDS.
It is thus well-known that the breast milk contains considerable amounts of urea. It is also known that the content of nitrogen not bound by proteins in breast milk is considerably higher than that corresponding to its content of urea. It has also been shown that this urea to some extent (about 20%) can be utilized as a substrate for the formation of alpha-aminonitrogen compounds, i.e. amino acids and proteins. Häussinger and co-workers [Häussihger D, Meijer A J, Gerok W, Sies H; “Hepatic nitrogen metabolism and acid-base homeostasis” in “pH homeostasis, mechanisms and control”, Ed D Häussihger, Academic Press Ltd, London (1988), pp 337-377] have by experiments shown that the ammonium nitrogen from the portal area, especially at acidosis, can be utilized for synthesis of glutamine in the liver. It is also known by intensive care physicians that ammonium chloride supplied intravenously and perorally lowers base excess values and such supply is accordingly used as a matter of routine for the treatment of a metabolic alkalosis. When the patient tre

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