Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-03-23
2002-04-09
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06369041
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the field of treating vitamin deficiency conditions and to preparations for use in such treatment.
BACKGROUND OF THE INVENTION
Vitamin B
12
is a cobalt-containing vitamin which is involved in a number of biochemical reactions. The two most important are the conversion of homocysteine to methionine and the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A. Homocysteine is potentially harmful to many body tissues, including the vascular system and the nervous system, if it is present in excess. Methionine is required for the formation of S-adenosyl-methionine which is used as a methyl donor in many different essential reactions including the regulation of DNA and RNA function and the synthesis of phospholipids, neurotransmitters and complex carbohydrates. The formation of succinyl-coenzyme A is required for the normal metabolism of fats and carbohydrates. It is thus apparent that an inadequate supply of vitamin B
12
will lead to many different abnormalities in the body. The best known are the haematological abnormality of megaloblastic anaemia, and neurological damage which can lead to fatigue and to a range of neurological and psychiatric symptoms which are caused by loss of neuronal function proceeding to neurodegeneration.
Vitamin B
12
has a particularly close interaction with folic acid. The conversion of homocysteine to methionine is achieved by the enzyme methionine synthetase where methyl-cobalamin plays an essential role. A required co-factor for this enzyme is folic acid in the form of 5-methyltetrahydrofolate: in the course of the reaction a methyl group is transferred from 5-methyltetrahydrofolate to homocysteine, so producing tetrahydrofolate and methionine. As a result of this reaction deficiencies of folic acid and of vitamin B
12
interact. This interaction is important both in the lowering of homocysteine and in the generation of S-adenosyl-methionine for methylation reactions.
Methylation is increasingly being recognised as a reaction of central importance in many different reactions in all the tissues of the body, but particularly the brain, the liver and rapidly dividing tissues like the bone marrow, the gastrointestinal tract, the skin and the reproductive system. The methyl donor which plays the key role in over thirty reactions is S-adenosyl-methionine (SAM) (T Bottiglieri et al, Drugs 1994; 48; 137-152. P K Chiang et al, FASEB J 1996; 10; 471-480. T Bottiglieri, Exp Opin Invest Drugs 1997; 6; 417-426. C S Lieber, J Hepatology 1999; 30; 1155-9). Methylation of the nucleic acids, DNA and RNA, plays a central role in the regulation of gene function and expression. Methylation regulates the functions of many enzymes, including enzymes involved in the synthesis of the neurotransmitters noradrenaline, dopamine and serotonin. Methylation modulates the behaviour of many receptors, including those for noradrenaline, adrenaline, acetyl choline, gamma-amino-butyric acid and many other substances. Methylation is important in the synthesis of key membrane phospholipids and in the regulation of the properties of all the external and internal phospholipid-containing membranes of cells. Methylation is required for the normal synthesis of the polyamines, spermine and spermidine, which are important signalling molecules in many cells. Methylation is important in the synthesis of complex carbohydrates which modify many cell-cell interactions. Since vitamin B
12
and folic acid are absolutely required for the normal synthesis of SAM, it is clear that it is of central importance that they should always be available in all tissues in adequate amounts. Recently, SAM and stable derivatives thereof have themselves been developed as drugs, particularly for nervous system and liver diseases (Bottiglieri, 1997, Lieber, 199).
As well as being converted to methionine, homocysteine can also be converted to cystathionine and then to cysteine in two successive reactions, both of which require vitamin B
6
as a co-factor. Excessive accumulation of homocysteine can thus be partially dealt with by its metabolism along this pathway. However, this cannot occur if there is inadequate availability of vitamin B
6.
Vitamin B
6
may, therefore, be of value in removing homocysteine, but not in generating SAM since it takes homocysteine out of the cycle.
There are four main forms of vitamin B
12
, cyanocobalamin, hydroxocobalamin, methylcobalamin and adenosylcobalamin. Methylcobalamin and adenosylcobalamin are unstable and very easily damaged by light. They are therefore unsuitable for use in dietary supplements or pharmaceuticals and are not necessary since they can be formed from cyanocobalamin or hydroxocobalamin within the body. The main form of vitamin B
12
found in food is hydroxocobalamin (J Farquharson and J F Adams, British Journal of Nutrition 1976; 36:127-136). The main form used therapeutically and in nutritional supplements is cyanocobalamin, chosen because it is the most stable form and therefore easiest to synthesise and formulate. All oral nutritional and pharmaceutical preparations of vitamin B
12
which are commonly available use cyanocobalamin.
In normal individuals vitamin B
12
is absorbed from the gastro-intestinal tract with the aid of a specific binding protein, known as intrinsic factor (IF) which is produced by the stomach. The normal daily requirement for vitamin B
12
is in the region of 0.1 to 2.0 microg/day according to various expert committees. There is normally an extensive enterohepatic recovery of vitamin B
12
. This recovery is impaired if IF is lacking, if the distal ileum is damaged, e.g. by radiation or disease, or has been removed by surgery. The daily loss of vitamin B
12
can be then considerably increased, at the same time as the food-bound vitamin B
12
cannot be absorbed. A lack of IF thus produces a deficit of vitamin B
12
within the body even though there are apparently adequate amounts in the food. The deficiency, known as pernicious anaemia, is treated by injections of vitamin B
12
as cyanocobalamin or hydroxocobalamin as it is generally believed that oral administration of vitamin B
12
will be ineffective.
However, it is not well known that it is possible to treat vitamin B
12
deficiency by oral administration of mg-doses even in the absence of IF, or when absorption is disturbed by other causes. This is because there is also a passive diffusion of the vitamin through the intestinal wall into the body without any need for IF. The passive absorption is dose-dependent and amounts to about 1-2% of doses of 1 mg or more. Two studies using cyanocobalamin have shown that oral doses of 1-2 mg/day are fully adequate to provide vitamin B
12
even in patients with pernicious anaemia (H Berlin et al, Acta Medica Scandinavica 1968; 184:247-258: A M Kuzminski et al, Blood 1998; 92:1191-8). Long-term oral treatment with 1 mg cyanocarbalamin per day has been calculated to restore the body stores of vitamin B
12
to the same extent as 1 mg hydroxocobalamin given by injection each third month (Berlin R et al, Acta Medica Scan. 1978; 204:81-4). However it is not well known by doctors that a vitamin B
12
deficiency can be treated orally: in a survey of 245 internal medicine specialists in Minnesota none had used oral vitamin B
12
to treated pernicious anaemia and only 1% had used oral vitamin B
12
to treat a dietary deficiency: injection of cyanocobalamin was the treatment used by those doctors (F A Lederle, JAMA 1991; 265:94-95).
Recent studies have demonstrated that vitamin B
12
deficiency states are much commoner in the general population, especially in the older population, in smokers, and in those at risk of cardiovascular disease than had previously been thought. One marker of this is an elevated level of homocysteine in plasma. For example, 44 apparently healthy men had elevated levels of homocysteine coupled with highly significantly subnormal blood levels of vitamin B
12
(J B Ubbink et al, American Journal of Clinical Nutrition 1993; 57:47-53). A high proportion of older outpatients att
Gouaille Christina
Horrobin David Frederick
Darby & Darby
Kilgowan Limited
Reamer James H.
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