WO2021191643A1

WO2021191643A1 - Compositions comprising deuterium depleted water for the normalization of leptin concentration in the body system

Info

Publication number: WO2021191643A1
Application number: PCT/HU2021/050022
Authority: WO
Inventors: Gábor SOMLYAI
Original assignee: Hyd Rákkutató És Gyógyszerfejlesztő Kft.
Priority date: 2020-03-26
Filing date: 2021-03-24
Publication date: 2021-09-30

Abstract

The primary object of the invention is deuterium-depleted water (DDW) with a deuterium content of 0.01 to 135 ppm for use in normalisation of leptin level in a mammal, preferably in a human. In a preferred embodiment of the invention, DDW is a component of a pharmaceutical composition or food product. The DDW for use according to the invention, and the above pharmaceutical compositions and food products which, owing to their reduced deuterium content, are suitable for the regulation of leptin level including the shifting of leptin levels towards the levels corresponding to age and gender, and thereby for the regulation of the basic metabolic rate of the body, and, through that, typically for the regulation of body mass, preferably for the prevention of obesity or cachexia.

Description

Compositions comprising deuterium depleted water for the normalization of leptin concentration in the body system

The invention relates to pharmaceutical compositions which, owing to their reduced deuterium content, are suitable for the regulation of leptin level including the normalisation of leptin levels, and thereby for the regulation of the basic metabolic rate of the body, and, through that, typically for the regulation of nutrition and body mass.

TECHNICAL BACKGROUND

According to our current knowledge, more than 400 genes are involved in the maintaining of appetite, metabolic functioning and body weight at a proper level for survival, which represents a severe practical obstacle to developing efficacious medicaments. This may explain that, due to this complex biological background, attempts at effectively addressing e.g. obesity, which is associated with several other comorbidities (diabetes, hypertension, increased cancer risk etc.), have not been successful so far.

During evolution, the lipid storage capacity of the body was a key factor in terms of survival. Unlike for people of our age, the availability, quality, and quantity of food were uncertain in the past. Therefore, if the circumstances permitted, the body stored energy in the form of lipids for times of limited food availability. Today it is recognised that during evolution, a highly precise mechanism regulating the energy balance, hunger sensation, lipid storage capacity, and body weight, was developed. (This, of course, is also present in animals.) One key component of this regulation is a hormone called leptin, which is released by adipose cells, and the binding of leptin to hypothalamic receptors ensures communication between the nervous system and adipose tissues.

The amount of leptin circulating in the body has been shown to be related to the amount of adipose tissue in the body. The fewer lipid storages are present, the less leptin will circulate in the blood. The less leptin is present, the bigger our appetite will be. This is how the body tries to restore “healthy” lipid storages. If adipose cells are saturated, the leptin level in the blood increases, which in turn reduces appetite via its effect on the nervous system, and thereby signals that no more energy intake is necessary. Serum leptin level (briefly, leptin concentration or leptin level) is an indicator of the energy state of the body, which means that leptin supplies information to the appetite and satiety centre about the lipid stores, that is, about the stores of energy in the body. Through certain mechanisms, leptin deficiency reduces the energy use of the body.

After leptin was discovered, it was generally accepted that leptin may be an effective tool in fighting obesity. This expectation was enhanced by the fact that in mouse experiment, the body weight of obese mice was normalised upon leptin injections, however, the results from the animal models could not be transferred into human practice. During a targeted clinical study started with an initial number of 73 volunteers was completed by 47 participants in the end as many prematurely withdrew from the study due to the adverse effects of leptin. The average body weight of the patients in the leptin group was reduced by 7.1 kg; however, surprisingly, body weight changes ranging from a reduction by 15 kg and to an increase by 5 kg were found within the group. This clinical study made it clear that leptin treatment cannot be simply translated into daily practice (Nature, vol. 404; 6 April, 2000), which is confirmed by the fact that no significant changes or medicaments has emerged in the pharmaceutical market since then.

A phase II clinical study of obese patients consuming deuterium-depleted water (DDW) surprisingly found significant changes in the leptin levels of their body. A gender- and age-independent evaluation of the data failed to show any appraisable relationship between leptin levels and obesity However, when the gender and age of the patients, and the normal leptin level of the given age group was taken into account, the changes in leptin levels - as a result of the reduction of deuterium (D) levels - was already appraisable, and it thus raises the possibility of using DDW as an active agent in order to normalise the leptin level of the body. The discovery of this effect of DDW offers an opportunity to beneficially influence such diseases of civilisation as obesity, hypertension etc. indirectly, via this mechanism. Leptin level normalisation may beneficially influence the energy balance and body weight of the individual from several directions. In case of individuals with a low body weight, a high leptin level conveys the message that fat depots are full and reduces appetite. A DDW-induced reduction of leptin levels may disengage this inhibition, may increase appetite, and thus normalise body weight. In the opposite case, when an obese individual has a low leptin level, this unjustifiably drives the individual towards additional energy intake via the sensation of hunger. If DDW induces an increase in the leptin level, then this may be accompanied by a reduced sensation of hunger, and subsequently, by a decrease in body weight. Often, the development of leptin resistance and not low leptin levels are responsible for obesity. In such cases, it may be assumed that a DDW-induced leptin level reduction may reduce leptin resistance in the long run. As regards insulin resistance, DDW was confirmed to have such effect. Obesity is considered as the primary cause triggering the so-called disease of civilisation. In the

US, 35% of the population is obese. In addition to diabetes, the risk of developing cardiovascular diseases and hypertension is also increased by a high percentage of adipose tissue within the body weight. Obesity- related health expenditure presents a burden of USD 190 billion on the economy of the United States.

The options for the prevention and treatment of obesity, and thereby diabetes, are limited. Despite powerful media communication, the encouragement of lifestyle changes failed to bring forth major changes in this field. Surgical treatment of obesity is expensive, and often involves severe health risks. The pharmaceutical industry developed two products for the treatment of obesity (Orlistat and Sibutramine), but the use of both products was accompanied by severe adverse effects while the achieved body weight reduction remained minimal (Sibutramine was removed from the market, and Orlistat is only available in a limited range of countries).

^'The main cause of developing obesity is that the body stores more energy than it needs. Leptin, which was discovered as the product of the ob gene during the late 1990s, represented one major development in the research of the regulation of the energy balance of the body (Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372:425-32, Friedman JM, Halaas JL.1998, Leptin and the regulation of body weight in mammals. Nature. 395: 763-770, Mantzoros CS. 1999. The role of leptin in human obesity and disease: a review of current evidence. Am Intern Med 130:671-680. Ahirna RS, Saper CB, Flier JS, Elmquist JK. 2000, Leptin regulation of neuroendocrine systems. Front Neuroendocrinol. 21:263-307). As it was revealed, the mechanism of action of leptin produced by adipose tissues increases energy use and reduces appetite and body weight primarily through hypothalamic receptors. Leptin reduces the amount of neuropeptides that increase appetite, while the amount of appetite -reducing neuropeptides also increases simultaneously. These results were confirmed by additional studies in die 2000s. (Schwartz MW, Porte D Jr. Diabetes, obesity, and the brain. Science 2005; 307:375-379. 15. Morton GJ, Schwartz MW. Leptin and the central nervous system control of glucose metabolism. Physiol Rev 2011; 91:389-411. 16.)

Unfortunately, excessive calorie intake may also lead to increased leptin levels without reducing appetite. In this case - similar to the development of insulin resistance -, the sensitivity of the body to leptin is lost, and therefore the patient overeats as the body senses starving.

SUMMARY OF THE INVENTION

The invention relates to the following:

1. Deuterium-depleted water (DDW) with a deuterium content of 0.01 to 135 ppm for use in normalisation of leptin level in a mammal, preferably in a human. 2. Deuterium-depleted water (DDW) for use according to item 1, wherein said DDW is a component of a pharmaceutical composition or food product.

3. Deuterium-depleted water (DDW) for use according to item 1 or 2, wherein the deuterium content of the water is 85 to 125 ppm.

4. Deuterium-depleted water (DDW) for use according to item 1 or 2, wherein the deuterium content of the water is 100 to 110 ppm, preferably 104 ± 1 ppm.

5. Deuterium-depleted water (DDW) for use according to item 1 or 2, wherein the deuterium content of the water is 25 to 84 ppm. 6. Deuterium-depleted water (DDW) for use according to any one of items 2 to 5, wherein the composition or product contains carbohydrates, amino acids, proteins and/or lipids with a deuterium content of 0.01 to 135 ppm, preferably 85 to 125 ppm.

7. A method of regulating leptin levels in a mammal, preferably in a human, characterised in that deuterium-depleted water (DDW) with a deuterium content of 0.01 to 135 ppm is administered to a subject in need thereof.

8. A method of regulating leptin levels in a mammal, preferably in a human, characterised in that a deuterium-depleted pharmaceutical composition or food product, with a deuterium content of 0.01 to 135 ppm is administered to a subject in need thereof. 9. The method according to item 7 or 8, wherein the deuterium content of the water or composition/product is 85 to 125 ppm, preferably 100 to 110 ppm, more preferably 104 ± 1 ppm.

10. The method according to item 7 or 8, wherein the deuterium content of the water or composition/product is 25 to 84 ppm.

As it was mentioned a number of times above, one preferable solution is that the deuterium content of the applied DDW or applied pharmaceutical composition or food product should be 85 to 125 ppm. Even more preferably, the deuterium content of the DDW or pharmaceutical composition or food product is 100 to 110 ppm, such as 104 ± 1 ppm. In addition, the reduced D level, typically a D level of 25 to 84 ppm, may be important because the consumption of such DDW may facilitate an earlier achievement of the desired reduction in the D level. The above levels may be applied in warm-blooded mammals, such as dogs and cats, where a D level of 25 to 84 ppm is typically used.

DETAILED DESCRIPTION OF THE INVENTION

With the advances in molecular biology, significant progress was made in exploring the biochemical processes regulating the basic metabolism of the body, body weight, and appetite in humans. What may explain that people take in more energy than their daily calorie need; and that people who are already severely obese are unable to reduce their daily calorie intake, which leads to further weight gain and the development of the associated diseases? The ob gene - which was discovered in the 1990s - and subsequent research made it clear that the central nervous system plays a key role in the regulation of glucose metabolism and of the energy homeostasis. As a result of a mutation in the ob gene, provided that it is present in both chromosome sets of the individual, the adipose tissue will not be able to synthesise the polypeptide called leptin. Leptin receptors are located in the hypothalamus, and leptin binding leads to a reduced appetite indicating that no more calorie intake is necessary. In case the body is unable to synthesise leptin, this sends an “I am starving” message to the body, and the individual consumes more calories than justifiable, which results in obesity, and subsequently diabetes. Later research confirmed the above thought by an independent observation (Hong Chen, at al. Evidence That the Diabetes Gene Encodes the Leptin Receptor: Identification of a Mutation in the Leptin Receptor Gene in db/db Mice Evidence That the Diabetes Gene Encodes the Leptin Receptor: Identification of a Mutation in the Leptin Receptor Gene in db/db Mice. Cell, Vol. 84, 491-495, February 9, 1996). The symptoms of the mice studied in this article were identical to those observed in mice with the genetic defect ob/ob (that is, mice not synthesising leptin) despite the fact that the adipose tissues of the mice were capable of synthesising leptin. These mice were found to have no receptors present in the hypothalamus as a result of the mutation ( db/db ); that is, although leptin was present in appropriate concentrations, the missing receptor prevented the body from being able to stop the uncontrolled energy intake. Further research underlined the fact that despite the presence of the hypothalamic leptin receptor, the energy homeostasis may still become disrupted due to a phenomenon similar to insulin resistance. In such cases, it is deduced that obesity develops because, despite the presence of leptin, the defective receptor is unable to send the appropriate message to the body by the central nervous system.

In view of the above, the fact that people suffering from insulin resistance and/or high blood sugar levels, and consuming deuterium-depleted water (DDW) showed significant changes in their leptin levels - an observation from a phase II human clinical study - is of particular importance. The primary objective of our studies was to confirm the effect of DDW on insulin resistance. In this context, patients consumed 1.5 L of DDW with a deuterium content of 104 ± 1 ppm for 90 days. (The starting date is important because Christmas came 60 days later, and the monitored parameters clearly indicated that the study participants significantly increased their calorie intake, which provides an explanation for the relative weight gain in that period; this also had to be taken into consideration during the evaluation.)

According to the study protocol, 30 individuals were planned to be enrolled. In order to identify the potential candidates, 42 individuals had to be tested to enable the enrolment into the clinical trial of 30 individuals meeting the inclusion criteria specified in the protocol. Accordingly, the 30 individuals thus enrolled were subjected to the appropriate treatment and follow-up for the entire study period. The relevant tables include a patient identifier (the original ones are applied without renumbering). The review of the leptin level data from the 30 individuals enrolled in the trial revealed a significant change from the average in one case, in case of patient No. 21. Whereas in 29 patients, the leptin levels showed a 1.3 to 2-fold change from baseline upon consuming DDW for 90 days, patient No. 21 showed a 23-fold change. It was assumed that this is the result of either a measurement error or an unknown reason, and therefore, the data from these patients were not included in subsequent calculations.

On the one hand, the results clearly confirmed our previous observation that DDW consumption reduced morning blood sugar levels, reduced insulin resistance in 30% of the patients, reduced morning insulin levels in half of the patients and showed a positive correlation with decreasing blood sugar levels. However, several other parameters were also monitored during the clinical trial, including leptin levels: Tables 2 to 4 show the changes in the blood leptin levels of the patients. Before rearranging the data, no clear conclusions may be drawn from the data presented in Tables 2 to 4 at first sight because they show minor or major changes in the leptin levels in both directions. However, when the fact that normal leptin levels show significant differences depending on the age and gender of the patient was taken into consideration [see Teresa Gijon-Conde, Auxiliadora Graciani, Pilar Guallar-Castillon, M. Teresa Aguilera, Fernando Rodriguez-Artalejo, Jose R. Banegas Leptin Reference Values and Cutoffs for Identifying Cardiometabolic Abnormalities in the Spanish Population. Rev Esp Cardial (2015) 68(8): 672-679, DOI: 10.1016/j.rec.2014.08.015], surprising relationships were revealed. Gender- and age-dependence data are summarised in Table 1.

Table 1

Average leptin levels in men and women depending on age

Next, the changes in the leptin levels were classified according to the degree of change from the normal value during the 90-day period of DDW consumption. Accordingly, if there is a change, then - in theory - 4 possible combinations exist: increase from a level below the normal decrease from a level above the normal further decrease from a level below the normal further increase from a level above the normal

When classifying the patients according to the above criteria, 11 out of the 30 patients showed an average decrease by 8.9 ng/mL from a level above the age- and gender-specific normal value (Table 2). 10 patients showed leptin levels below the age- and gender-specific normal value but increased by 12.2 ng/mL on average (Table 3). In another 9 cases (Table 4) levels above the age- and gender-specific normal value showed further increase (by 10.3 ng/mL on average); however, cases with further reductions of a below- normal leptin level were not detected. In summary, the data suggests that 66% of the patients showed leptin level changes towards the normal range, that is, the results also indicate that DDW consumption mostly has the effect of shifting leptin levels towards the normal range. In the other cases, leptin levels increased, which is normally beneficial in terms of losing weight, i.e., if it is considered an important factor then the small number of cases showing increases towards the normal leptin levels may be regarded as advantageous in these terms.

The fact that - unlike several pharmaceutical compositions - DDW consumption is able to shift the value of the given parameter towards more than one direction but could increase low values and decrease high values, confers particular importance to this observation.

Conclusions that can be drawn from the results include:

1. As a result of DDW consumption, the subjects showed significant changes in their serum leptin levels. 2. The direction of the changes in the leptin levels were typically dependent on whether leptin levels were below or above the normal value at baseline, before the clinical trial.

3. In 66% of the patients, leptin levels shifted towards the range characterising the given gender and age group.

4. Consumption of water and/or food products with a low deuterium content provides an opportunity to influence the effect on the basic metabolic rate of the body through changing leptin level affecting the central nervous system.

5. The results also demonstrate that the leptin level-adjusting effect of DDW is associated with a favourable effect on the insulin balance of individuals with insulin resistance and/or high blood sugar levels. Therefore, the experiments gave rise to a surprising result that changes in the deuterium level in the body influenced the blood level of leptin produced by the adipose tissues. One particularly interesting feature of this clinical trial was that while all patients uniformly showed a reduction in their deuterium level, its effect on leptin depended on the actual level of leptin and on the relationship between that level and the normal value corresponding to the age and gender of the person in question. Thus, leptin level normalisation is intended to mean that the leptin levels are shifted towards the age- and gender-specific normal level. That is, more specifically, the invention relates to the use of DDW for adjusting leptin levels to the age- and gender-specific values. ft is widely recognised that a daily fluid consumption rate of 1.2 to 1.5 L is accompanied by the production of 0.2 to 0.3 L of so-called metabolic water generated by the degradation of organic compounds in the body. In order to prevent the normal deuterium content of this metabolic water - provided that the organic compounds were generated under natural circumstances - from weakening the effect of the deuterium-depleted water, the implementation of the invention is supported by the discovery that during the consumption of organic compounds (carbohydrates, amino acids, and lipids) with a lower-than-natural deuterium (D) content, the reduction of the D levels in the body provides further opportunities to influence leptin level.

Based on the above, in a preferred embodiment of the use according to the invention, water (DDW) with a deuterium content of 0.01 to 135 ppm - that is, a HDO content of 0.021 to 287 mg/L - is used. In another embodiment, a pharmaceutical composition containing DDW is used. This pharmaceutical composition may be e.g. a DDW-based isotonic infusion, which may optionally contain other salts ad/or active ingredients. The pharmaceutical composition may contain carbohydrates, amino acids, proteins, and lipids comprising less-than-natural levels of deuterium (0.01 to 135 ppm), wherein the water content is obviously DDW. It may also contain carbohydrates, amino acids, proteins, and lipids comprising less-than- natural levels of deuterium (0.01 to 135 ppm), wherein the water content is obviously DDW. Furthermore, food products (such as soups, pastas, bread products, cooked vegetable dishes etc.) may be produced with the use of DDW instead of water; thus, such food products will contain DDW instead of normal water added during production, and therefore, will have a reduced D content (0.01 to 135 ppm, preferably 85 to 125 ppm).

Our experiments suggest that within the indicated range, a deuterium content of 85 to 125 ppm (that is, a HDO content of 178 to 262 mg/L) is preferable. More preferably, the D content is 100 to 110 ppm, such as 104 ± 1 ppm. A D level of 25 to 84 ppm (that is, a HDO level of 52 to 175 mg/L) may also be preferable.

The D content of natural water is reduced to a level of 0.01 to 135 ppm (0,021 to 287 mg/L HDO) using a method known per se, suitably by electrolysis or distillation, and then the water with a D content of 0.01 to 135 ppm (0,021 to 287 mg/L HDO) is either used directly or used for the preparation of deuterium- depleted carbohydrates, amino acids, proteins, and lipids. For example, this may be achieved in the following ways: a) Preparation of deuterium-depleted food products

Pepper, tomato, pea, green bean etc. plants are grown using water with a D content of 0.01 to 135 ppm and known plant production methods. The plants are then processed into food products using the usual food production methods. b) Preparation of deuterium-depleted carbohydrates (sugars)

Water with a D content of 0.01 to 135 ppm, that is, a HDO content of 0.021 to 287 mg/L, is used for irrigation, preferably in the greenhouse cultivation of the sugar beet, a plant with high sugar content. Carbohydrates are extracted from the plants produced using deuterium-depleted water using a method widely used in sugar beet processing. c) Preparation of deuterium-depleted proteins Water with a D content of 0.01 to 135 ppm, that is, a HDO content of 0.021 to 287 mg/L, is used for irrigation, preferably in the greenhouse cultivation of soybean, a plant with high protein content. The plants produced using deuterium-depleted water are processed using methods widely used in the food and feed sector. d) Preparation of deuterium-depleted lipids and oils

Water with a D content of 0.01 to 135 ppm, that is, a HDO content of 0.021 to 287 mg/L, is used for irrigation, preferably in the greenhouse cultivation of sunflower, plant with high oil content. The plants produced using deuterium-depleted water are processed using methods widely used in the food and feed sector. e) Preparation of deuterium-depleted foods with high protein and lipid contents

The plants produced using irrigation water with a D content of 0.01 to 135 ppm, that is, a HDO content of 0.021 to 287 mg/L, are processed using method widely used in the feed sector. The thus prepared deuterium-depleted feed product is used for feeding agricultural animals, while simultaneously replacing the drinking water of the animals with water with a D content of 0.01 to 135 ppm, that is, a HDO content of 0.021 to 287 mg/L. The animals to be slaughtered are processed using the usual food production methods.

The DDW and/or the carbohydrates, amino acids, proteins, and lipids are processed into pharmaceutical compositions upon mixing with the usual pharmaceutical carriers and/or auxiliaries using usual methods applied in the pharmacological practice, or into food products using the usual food production methods. The deuterium-depleted carbohydrates, amino acids, proteins, and lipids are suitably prepared using water with a deuterium content of 0.01 to 135 ppm, that is, a HDO content of 0.021 to 287 mg/L in plant production and animal farming.

Consistently, it can be stated that the raw materials and food products prepared according to points (a) to (e) above have a natural water content with reduced deuterium levels (DDW).

Among the options of preparing deuterium-depleted water, special emphasis is placed on electrolysis and distillation, which enable mass production of DDW at a relatively low specific cost. a) Aqueous KOH solution of 15 to 20 % is electrolysed with 2 to 5 V DC on separated anode and cathode. Hydrogen with reduced deuterium content, released at the cathode, is burnt and the water vapour obtained is condensed in a distillation system and collected separately. The D content of the water thus obtained is 30 to 40 ppm. (Separation of Hydrogen Isotopes Eds.:Howard K. Rae, American Chemical Society Symposium Series 68, Washington D.C. 1978; Isotope Separation Eds.: Stelio Villani, American Nuclear Society 1983). The D content of the water thus obtained may be further reduced by electrolysis. b) Distilled water is boiled at a pressure of 50 to 60 mbar and a temperature of 45 to 50°C, in a distillation tower with plate number of 50 to 150 suitable for fractional distillation. During distillation, the reflux value is 12 to 13, and the bottom return rate in the vat is 10-fold. The D content of the head product ranges between 0.1 and 30 ppm if such parameters are used (Separation of Hydrogen Isotopes, Eds.:Howard K. Rae, American Chemical Society Symposium Series 68, Washington D.C. 1978; Isotope Separation Eds.: Stelio Villani, American Nuclear Society 1983). During the operation of the column, changing the parameters - for example, significantly increasing the column load - also enables the production of large quantities of water with a D content of more than 30 ppm. Another option is to further deplete the D content of the deuterium-depleted water obtained from the column by subjecting it to further fractional distillation on a similar, coupled column (or columns).

The use forming the basis of the present invention may be used for the normalisation of the leptin level in the body, for the normalisation of the basic metabolic rate, and optionally, for body weight reduction. This is based on the fact that D level in the body decreases during the administration of DDW and DDW-containing pharmaceutical compositions (e.g. solutions) and/or deuterium-depleted carbohydrates, amino acids, proteins, and lipids, which in turn normalises leptin level. In case normalisation means reducing the leptin level, calorie intake and body weight preferably decreases, and the energy balance of the body becomes normalised, which may prevent obesity, diabetes, and insulin resistance. In the above-mentioned cases, the active ingredient (which may be DDW and/or deuterium- depleted carbohydrates, amino acids, proteins, and lipids, or other deuterium-depleted food products) may be used in combination with other inert, non-toxic auxiliaries (e.g. flavours, salt and sugar substitutes). Fluid active ingredients may be formulated into pharmaceutical compositions for oral (e.g. solution, emulsion, suspension etc.) or for parenteral (e.g. infusion solution) administration. The pharmaceutical compositions are prepared using pharmaceutical methods known per se, upon mixing the active ingredient with inert, inorganic or organic carriers, and then formulating the mixture into a galenic form. Pharmaceutical compositions may also contain additional usual pharmaceutical auxiliaries (for example, wetting agents, sweeteners, aromas, buffer solutions etc.).

The daily dose of the pharmaceutical compositions may be changed within a wide range, and depends on several factors, such as the D content of water, the weight, gender, and age of the patient, and the leptin level / degree of leptin resistance etc. The oral daily dose for a patient with a body weight of 70 kg may be 0.01 to 2 litres of DDW with a D content ranging from 0.01 to 135 ppm. Partly for the purpose of enhancing the organoleptic value, and partly for increasing the effects, the water may contain 20 to 30 grams of deuterium-depleted carbohydrates, or certain deuterium-depleted amino acids, and other flavours and aromas.

The key advantages of the composition and method of the invention include: a) Enables the normalisation of the leptin level in the body. b) Enables the normalisation of the body weight and basic metabolic rate of the subjects. c) Enables prevention of obesity, and reduces body weight in already overweight, obese individuals. In case of an abnormally low body weight, a beneficial increase in the body weight is expected upon the normalisation of the leptin level. d) Normalisation of the leptin level may reduce the risk of developing the group of symptoms belonging to the diseases of civilisation (diabetes, hypertension, cardiovascular diseases). This is because abnormal leptin levels may raise the possibility of developing metabolic syndrome (Wen-Cheng Li, Kuang- Yu Hsiao, I-Chuan Chen, Yu-Che Chang, Shih-Hao Wang and Kuan-Han Wu: Serum leptin is associated with cardiometabolic risk and predicts metabolic syndrome in Taiwanese adults. Cardiovascular Diabetology 2011, 10:36) e) The compounds used during the method do not produce a toxic effect or immune reaction. f) The preparation of the compositions is simple, and no hazardous waste is generated during the manufacturing.

EXAMPLES Without limiting its scope, the invention is more specifically disclosed via the following examples.

A) Pharmacological example

In the study enrolling 30 volunteers with reduced glucose tolerance and monitoring other parameters too, the effect of consuming deuterium-depleted water (DDW) for 90 days on the serum leptin levels was investigated. All patients consumed 1.5 litres of DDW with a deuterium content of 104 ± 1 ppm as drinking water, irrespective of their body weight. The D levels in the serum of the volunteers decreased from a baseline of 147.5 ± 0.8 ppm to 133.9 ± 4.1 ppm by the and of the study (pO.OOOl).

Leptin level data (together with other relevant data) are presented in the following tables.

Table 2

In case of the negative values, leptin levels diverge downward from the normal value; in such cases, the total (‘Total’) and the average (‘Average’) values were calculated using the absolute value of the negative numbers to prevent the “improvement” of the calculated values caused by differences having opposite signs.

Table 2 shows that leptin levels decreased highly significantly as a result of the DDW treatment in patients with leptin levels above the age- and gender specific normal value (by an average degree of 7.5 ng/mL). The values measured on Day 90 were always closer to the normal level (and were below the normal level only minimally, and only in two cases). Table 3

In case of the negative values, leptin levels diverge downward from the normal value; in such cases, the total (‘Total’) and the average (‘Average’) values were calculated using the absolute value of the negative numbers to prevent the “improvement” of the calculated values caused by differences having opposite signs. Therefore, the total (‘Total’) and average (‘Average’) values are expressed as positive values.

Table 3 shows that leptin levels increased as a result of the DDW treatment in patients with leptin levels below the age- and gender specific normal value (by an average degree of 1.4 ng/mL). The average values measured on Day 90 were closer to the normal levels. Table 4

Table 4 shows that as a result of the DDW treatment, approximately one third of the patients showed an increased leptin level despite the fact that their baseline level was above the age- and gender- specific normal value (the average value increased by 10.3 ng/mL). It is noted that because increased leptin levels facilitate weight loss in theory, the above (small number of) cases of exceeding the normal leptin levels may be advantageous in these terms.

B) Formulation examples

Formulation example 1

Preparation of drinking water with a preferable salt composition

Deuterium-depleted water is mixed with a mineral water of known salt composition (Csillaghegyi or Balfi mineral water) in the following ratio: a) 0.25 volume of water with a D content of 90 ppm + 0.75 volume of mineral water (final D concentration: 135 ppm) b) 0.5 volume of water with a D content of 90 ppm + 0.5 volume of mineral water (final D concentration: 120 ppm) c) 0.75 volume of water with a D content of 90 ppm + 0.25 volume of mineral water (final D concentration: 105 ppm) d) 0.25 volume of water with a D content of 60 ppm + 0.75 volume of mineral water (final D concentration: 127.5 ppm) e) 0.5 volume of water with a D content of 60 ppm + 0.5 volume of mineral water (final D concentration: 105 ppm)

Formulation example 2

The cation and anion concentration of deuterium-depleted water is adjusted using an artificially prepared concentrate having preferred salt composition.

A possible composition of the stock solution may be as follows:

KC1 5.7 g

MgC1₂ x 6 H₂0 199.65 g

CaC1₂ x 6 H₂0 236.25 g

Upon adding the stock solution thus obtained to 1000 litres of Dd water, the following final concentrations are achieved: 23.8 mg/L Mg ²⁺. 64.1 mg/L Ca ²⁺, 3 mg/L K⁺, 192 mg/L C1-.

Formulation example 3

The isotonic nature of the deuterium-depleted water is ensured by adding sodium salts.

A possible composition of the stock solution may be as follows:

NaHC0₃ 500 g

NaC1 500 g

Upon adding the stock solution thus obtained to 1000 litres of Dd water, the following final concentrations are achieved: 417 mg/L Na⁺, 304 mg/L C1-, 279 mg/L HC0₃-.

Claims

1. Deuterium-depleted water (DDW) with a deuterium content of 0.01 to 135 ppm for use in normalisation of leptin level in a mammal, preferably in a human.

2. Deuterium-depleted water (DDW) for use according to claim 1, wherein said DDW is a component of a pharmaceutical composition or food product.

3. Deuterium-depleted water (DDW) for use according to claim 1 or 2, wherein the deuterium content of the water is 85 to 125 ppm.

4. Deuterium-depleted water (DDW) for use according to claim 1 or 2, wherein the deuterium content of the water is 100 to 110 ppm, preferably 104 ± 1 ppm.

5. Deuterium-depleted water (DDW) for use according to claim 1 or 2, wherein the deuterium content of the water is 25 to 84 ppm.

6. Deuterium-depleted water (DDW) for use according to any one of claims 2 to 5, wherein the composition or product contains carbohydrates, amino acids, proteins and/or lipids with a deuterium content of 0.01 to 135 ppm, preferably 85 to 125 ppm.

8. A method of regulating leptin levels in a mammal, preferably in a human, characterised in that a deuterium-depleted pharmaceutical composition or food product, with a deuterium content of 0.01 to 135 ppm is administered to a subject in need thereof.

9. The method according to claim 7 or 8, wherein the deuterium content of the water or composition/product is 85 to 125 ppm, preferably 100 to 110 ppm, more preferably 104 ± 1 ppm.

10. The method according to claim 7 or 8, wherein the deuterium content of the water or composition/product is 25 to 84 ppm.