IE80469B1

IE80469B1 - Compositions for reducing fluctuations in plasma concentrations of large neutral amino acids and use thereof in therapy

Info

Publication number: IE80469B1
Application number: IE930676A
Authority: IE
Inventors: Kenneth William Henry Mcvey; Michael Sember
Original assignee: Elan Corp Plc
Priority date: 1993-09-13
Filing date: 1993-09-13
Publication date: 1998-07-29
Also published as: GB9418370D0; GB2282048A; ZA946998B; IE930676A1; JPH07278009A; GB2282048B

Abstract

Nutritionally complete food product compositions are provided which have a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, preferably 7:1, the protein component having a protein efficiency ratio (PER) of greater than or equal to 2.5. The compositions are used to reduce fluctuations in plasma concentrations, especially post-prandial fluctuations, of large neutral amino acid (LNAA) levels and have particular use in the treatment of individuals suffering from Parkinson's Disease to reduce the variability of the individuals' response to a LNAA drug such as L-dopa, alpha -methyldopa or 5-hydroxytryptophan. The compositions can be in the form of liquid formulations, including soups, and reconstitutable powders for forming such formulations, snack bars, entrees and desserts.

Description

Compositions for reducing fluctuations in plasma concentrations of large neutral amino acids and use thereof in therapy Parkinson's Disease (PD), one of the most common neurological disorders of ageing, is a chronic degenerative disorder of the basal ganglia. Treatment of PD typically includes administering to the PD patient a drug that is capable of enhancing dopamine, such as L-dopa, α-methyldopa and 5-hydroxytryptophan, either singly or in combination with a dopa decarboylase inhibitor, such as carbidopa. Administration of the dopamine enhancing drugs, which are large neutral amino acids (LNAAs), results in a replenishment of the patient's dopamine stores. However, patients who take such drugs may experience variability in response to the treatment regime and may suffer adverse effects, such as L-dopa-induced dyskinesia and/or exacerbated Parkinsonian symptoms.

Some of the adverse effects experienced by the patient being treated with L-dopa or a similar dopamine enhancing drug stem from the nature of the drug itself. That is, in order for the drug to restore brain dopamine levels, it must first pass from the blood into the substance of the brain. Competition with LNAAs at the blood brain barrier limits the entry of L-dopa, which is itself an LNAA. Thus, the quantity of L-dopa entering the brain depends not only on plasma Ldopa levels but also on plasma LNAA levels. If the level of L-dopa in the brain is too high, the patient can experience abnormal movements (dyskinesias); if the level is too low, the Parkinsonian symptoms can be exacerbated.

Post-prandial plasma LNAA levels can vary widely in a patient and are affected by the carbohydrate and protein content of the food consumed. Consumption of a high protein meal elevates plasma levels of LNAAs, interfering with transport of L-dopa across the blood brain ' 30 barrier and, if the supply of L-dopa to the brain is insufficient, resulting in manifestation of Parkinsonian symptoms. In contrast, consumption of a high carbohydrate meal, through the action of insulin, dramatically lowers plasma levels of some LNAAs. This decrease may cause too much circulating L-dopa to enter the brain, resulting in L-dopa induced toxicity.

Diet manipulation to control PD has been attempted. For instance, U.S. Patent No. 5,206,218 describes compositions and methods for reducing post-prandial fluctuations in plasma levels of LNAAs that relate to the administration of food or compositions having a carbohydrate to protein ratio of from about 3:1 to about 6:1. Similarly, Berry et al. (Neurology, 47; 1295-1297 (1991)) report that plasma LNAA levels varied less and motor performance was superior for PD patients during the two hours following a breakfast in which the carbohydrate to protein ratio was 5:1 compared to an isocaloric high carbohydrate breakfast or an isocaloric high protein breakfast. Restricted protein diets have also been recommended, including those that restrict the protein intake during the day followed by a high protein supper (see, e.g., Pare et al., Am. J. Clin. Nutr., 55; 701-7 (1992)). Although this dietary manipulation may, at least temporarily, increase therapeutic effectiveness, several problems have been associated with restricted day-time protein intake: (1) side-effects such as excessive brain uptake of L-dopa leading to confusion and dyskinesia; (2) inadequate daily protein consumption; (3) inhibition of the therapeutic effects of L-dopa in the evening due to excessive dinner time protein intake; (4) weight loss due to decreased caloric intake associated with day-time protein restriction; and (5) reduced calcium intake. These problems are especially important in patients with PD because it is known that the disease process itself typically results in (1) an increased caloric requirement (perhaps secondary to the abnormal movements) for the patient and (2) a decreased caloric intake (due to slowness in eating and difficulties in chewing and swallowing).

Thus, there exists a need for compositions that are capable of being administered to an individual to reduce fluctuations, such as postprandial fluctuations, in plasma concentrations of LNAAs while providing complete nutrition, especially protein, caloric, vitamin and mineral nutrition, to the individual over a period of time. In particular, there exists a need for compositions that can be administered at various times over the course of a day to an individual being treated with a drug which itself is a LNAA, whereby the compositions are optimally balanced with respect to carbohydrate and protein to provide for reduced variability of the individual's response to the LNAA drug.

The invention provides in a first aspect a nutritionally complete food product composition for administration to an individual to reduce fluctuations in plasma concentrations of large neutral amino acid levels, having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, wherein the protein has a protein efficiency ratio (PER) of greater than or equal to 2.5.

The invention provides in a second aspect a nutritionally complete food product composition for use in repeated administrations to an individual over a predetermined period of time to sustain reduced fluctuations in plasma concentrations of large neutral amino acid levels for that predetermined period of time, having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, wherein the protein has a protein efficiency ratio (PER) of greater than or equal to 2.5.

The invention provides in a third aspect a nutritionally complete food product composition for administration to an individual to reduce the variability of response to a large neutral amino acid drug in the individual, having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, wherein the protein has a protein efficiency ratio (PER) of greater than or equal to 2.5.

The carbohydrate to protein ratio of the compositions according to the invention is preferably of the order of 7:1.

Further, preferably, the composition is in the form of a liquid formulation, a dehydrated powder capable of being reconstituted to form a liquid formulation, a soup, a dehydrated composition capable of being reconstituted to form a soup, a snack bar, an entree or a dessert.

Also preferably when the composition is intended for administration on a repeated basis to an individual over a predetermined period of time, said predetermined period of time is selected from 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours and 1 week.

When the composition according to the invention is used to reduce the variability of response to a LNAA drug, said drug is suitably selected from L-dopa, α-methyldopa and 5hydroxytryptophan.

Suitably, the compositions according to the invention have a calorific content of approximately 400 to 600 calories.

The protein component of the compositions according to the invention in its different aspects is suitably selected from casein, caseinate, whey protein concentrate, lactalbumin, milk protein isolate, non-fat dry milk, egg white, 50:50 lactalbumin/soy protein isolate, 75:25 casein/soy protein isolate, 50:50 milk protein isolate/wheat protein and 50:50 lactalbumin/wheat protein.

Brief description of the drawings Fig. 1 is a bar chart showing the percentage change in the plasma LNAA levels of healthy adults at intervals of one and three hours after ingesting a drink with a carbohydrate: protein ratio of between 4:1 and 8:1 as described in Example 1, and; Fig. 2 is a graph showing the variation in the sum of LNAA over a time period during which two drinks of a given carbohydrate: protein ration were ingested as described in Example 2.

As used herein, LNAA includes amino acids which have a single amino group and a single carboxyl group, for example, leucine, isoleucine, tyrosine, valine, phenylalanine and tryptophan. The terms nutritionally complete or complete nutrition refer to compositions which, in addition to carbohydrate, protein and fat, contain amounts of essential vitamins and minerals substantially in US RDA (Recommended Daily Allowance) or US RDI (Recommended Daily Intake) proportion to the caloric content of the composition. Reduction in fluctuations (such as post-prandial fluctuations) in an individual's plasma concentrations of LNAAs refers to control over the LNAA levels (such as post-prandial) in such a manner that they exhibit less variation than is evident when the individual being treated consumes his or her usual diet.

The present invention is based upon the discovery that compositions having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, preferably 7:1, in which the protein efficiency ratio (PER) rating for the protein is greater than or equal to 2.5, surprisingly optimise the reduction in fluctuations, such as postprandial fluctuations, in plasma LNAA levels of an individual to which the compositions are administered. These compositions minimize the post-prandial fluctuations compared to compositions containing carbohydrate to protein ratios of 3:1 to 6:1. Further, because of the high PER rating of the protein, the individuals receiving these compositions also receive nutritionally adequate amounts of protein from these compositions relative to their caloric content. These nutritionally complete compositions can be administered to an individual, particularly a PD patient, to reduce the variability of the individual's response to a LNAA drug (or drugs), such as L-dopa or a similar drug. In this way, the amount of drug necessary for treatment can be administered beneficially without provoking either under medication or drug toxicity symptoms over a selected period of time, such as over a short time period following a single dosage (hours) or over an extended period of time following multiple administrations (hours, days, weeks, months). Importantly, the present invention allows not only for LNAA drug dosing with minimized side effects but also provides the individual with complete nutrition, including adequate amounts of proportion with the caloric content of each administration, thus overcoming the prior art problems discussed above. As such, repeated administration of these nutritionally complete food product compositions, such as four times a day in place of regular meals and/or snacks, while providing beneficial control over fluctuations in the plasma concentrations of LNAAs, do not promote protein/nitrogen deficits and other associated problems such as weight loss. Thus, patients receiving a LNAA drug, such as PD patients on L-dopa, beneficially can ingest these compositions in place of all or some of their daily meals and/or snacks.

The nutritionally complete food product compositions of the present invention can be formulated conveniently in the form of liquid formulations, such as chocolate, strawberry, vanilla or other-flavoured drinks; dehydrated powders, such as those that can be hydrated to form drinks similar to the flavoured liquid formulations discussed above; soups, such as chicken, turkey, beef, or vegetable soups and the like; dehydrated compositions capable of being reconstituted to provide soups similar to those discussed above; snack bars, entrees, such as spaghetti-containing formulations; and desserts as well as other convenient, ingestable formulations.

In addition to providing complete nutrition, the ratio of carbohydrate to protein in the present food product compositions ranges from greater than 6:1 to less than 8:1, preferably 7:1. For instance, individuals treated with the compositions given herein typically will receive approximately 2000 calories/day in four portions. An approximately 500 calorie serving containing a protein (PER > 2.5) content of 13g (slightly more than one-fourth the recommended 45g daily allowance for protein having a PER of 2.5 or greater as shown in Table 1 below) contains approximately more than 78g to less than 104g carbohydrate and approximately 16g to 3.75g fat. As can be appreciated from Table 1 below, because the ratio of carbohydrate to protein is so high, inclusion of protein having a PER less than 2.5 into a formulation typically would result in a protein deficient diet, especially if the formulation was taken exclusively over a period of time. Ί TABLE 1 Nutrient and unit of measurement U.S. RDA1 Amount per 100 kcal Protein (g)265 45 3.25 2.25 Vitamin A (IU) 5000 250 Vitamin C (mg) 60 3 Thiamine (mg) 1.5 0.075 Riboflavin (mg) 1.7 0.085 Niacin (mg) 20 1.0 Calcium (g) 1 0.05 Iron (mg) 18 0.9 Vitamin D (IU) 400 20 Vitamin E (IU) 30 1.5 Vitamin B-6 (mg) 2 0.1 Folic acid (mg) 0.4 0.02 Vitamin B-12 (ug) 6 0.3 Phosphorus (g) 1 0.05 Iodine (ug) (optional) 150 7.5 Magnesium (mg) 400 20 Zinc (mg) 15 0.75 Copper (mg) 2 0.1 Biotin (mg) 0.3 0.015 Pantothenic acid (mg) 10 0.5 1. U.S. Recommended Daily Allowance for adults and children 4 or more years of age. 2. If the protein efficiency ratio of protein is equal to or better than that of casein, the U.S. RDA is 45g.

The protein component of the nutritionally complete food product compositions disclosed herein can be any animal or vegetable protein, or combination of proteins, having a PER greater than or equal to 2.5. However, casein/caseinate is a preferred protein. Table 2 gives PER values for representative proteins or protein mixtures.

TABLE 2 Protein Efficiency Ratios of Food Proteins or Complementary Protein Blends PROTEIN TYPE PER Whey protein concentrate 3.0 Lactalbumin 2.9 Milk 2.8 Milk protein isolate 2.8 Casein/caseinate 2.5 Non-fat dry milk 2.7 Egg white 2.8 Rice protein 2.2 Soy protein isolate 1.8 Wheat gluten 1.1 Lactalbumin/soy protein isolate (50:50) 2.5 Casein/soy protein isolate (75:25) 2.5 Milk protein isolate/wheat protein (50:50) 2.5 Lactalbumin/wheat protein (50:50) 2.5 The nutritional information for a representative formulation for a dehydrated powder capable of being reconstituted to form a liquid formulation or chocolate milk-shake is given in Table 3 below. Such a formulation typically includes maltodextrin, sugar, calcium caseinate, canola oil, Dutch processed cocoa, Soy fibre, silicon dioxide (anticaking agent), gum guar, natural and artificial flavours, and the following vitamins and minerals: potassium chloride, sodium phosphate, calcium phosphate, magnesium chloride, magnesium oxide, magnesium carbonate, sodium chloride, sodium ascorbate, molybdenum yeast, vitamin E acetate, choline bitartrate, selenium yeast, chromium yeast, ferric orthophosphate, vitamin A palmitate, niacinamide, zinc oxide, copper gluconate, D-calcium pantothenate, manganese sulphate, vitamin D3, pyridoxine hydrochloride, riboflavin, thiamine mononitrate, folic acid, biotin, potassium iodide, vitamin Ki, and vitamin B12.

TABLE 3 NUTRITIONAL INFORMATION Amount per serving Calories (cal) 497 Calories from fat (cal) 81 Carbohydrate (less fibre) (g) 91 Protein (g) 13 Fat (g) 9 Saturated fat (g) 1.3 Cholesterol (mg) less than 5 Sodium (mg) 195 Potassium (mg) 385 Dietary fibre (g) 4 %RDI Vitamin A 25.0 Vitamin C 75.0 Calcium 25.0 Iron 25.0 Vitamin D 25.0 Vitamin E 50.0 Thiamine 25.0 Riboflavin 25.0 Niacin 25.0 Vitamin B6 25.0 Folate 25.0 Contd/...

TABLE 3 contd.

Vitamin B12 25.0 Biotin 25.0 Pantothenic Acid 25.0 Phosphorus 25.0 Iodine 25.0 Magnesium 25.0 Zinc 25.0 Copper 25.0 Manganese 25.0 Choline * Chloride * Vitamin K * Chromium * Molybdenum * Selenium * *RDI has not been established.

The above powder formulation would typically be reconstituted in about 228 ml of water.

The food product compositions according to the invention can be manufactured and packaged according to known processes. For instance, to make a representative vanilla-flavoured liquid formulation, deionized water is heated to 65-70°C. To this water, Maltrin 200 (Maltrin 200 is a Trade Mark), calcium caseinate, sodium caseinate, soy polysaccharide, gum concentrate, and sucrose is added. In a separate container, Atmul 84 (Atmul 84 is a Trade Mark) and soy lecithin is added to canola oil and heated to 65°C. After the oil mixture is added to the water mixture, the minerals and potassium hydroxide (mixed with cold deionized water) are added; the mixture is held for 30 minutes and then the vitamins and vanilla flavouring are added and held for 10 minutes. This mixture is pumped through an on-line homogenizer (1,800-2,000 psi) and then (heated to 75°C) homogenized a second time at 500 psi/second stage; 2,500 psi/first stage. The product is heated to 80°C-90°C for 20 seconds and cooled to less than 12°C. During the latter UHT (ultra high temperature) process, the product is homogenized again through the on-line homogenizer (500 psi/second stage; 2,000 psi/total). The liquid is packaged into appropriate package (i.e., 12 oz) with straw and pull tab.

According to a fourth aspect of the invention there is provided use of a nutritionally complete food product composition having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, wherein the protein has a protein efficiency ratio (PER) of greater than or equal to 2.5 in the manufacture of a medicament for use in a method of reducing fluctuations in plasma concentrations of large neutral amino acid levels.

According to a fifth aspect of the invention there is provided use of a nutritionally complete food product composition having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, wherein the protein has a protein efficiency ratio (PER) of greater than or equal to 2.5 in the manufacture of a medicament for use in a method of sustaining reduced fluctuations in plasma concentrations of large neutral amino acid levels for a predetermined period of time.

According to a sixth aspect of the invention there is provided use of a nutritionally complete food product composition having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, wherein the protein has a protein efficiency ratio (PER) of greater than or equal to 2.5 in the manufacture of a medicament for use in a method of reducing the variability of response to a drug which is a large neutral amino acid in an individual.

According to the present invention, an effective quantity of a nutritionally complete food product composition or food having a carbohydrate to protein ratio of from greater than 6:1 to less than 8:1, preferably 7:1, and having protein ranking at or above 2.5 PER as hereinabove defined can be administered to an individual to reduce fluctuations, for example post-prandial fluctuations, in plasma concentrations of LNAA levels. For instance, an approximately 500 calorie serving can be ingested by a PD patient in place of at least one usual meal to provide for control over the fluctuations in plasma concentrations of LNAA such that less variation in the LNAA levels is evident than when the individual being treated consumes his or her usual diet. This result can be observed over the following hours (e.g., 2 hours, 4 hours etc.). Of course, multiple usual meals and/or snacks can be replaced by the compositions of the present invention. Because the food product compositions are nutritionally complete and contain adequate protein to prevent protein depletion, the present compositions can sequentially replace any number of usual meals, thus providing for sustained reduction of fluctuations in plasma concentrations of LNAA levels over a predetermined period of time, such as 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, weeks etc. Of course, the present compositions or foods can be administered to individuals to reduce the variability in a patient's clinical responses to treatment with drugs which are LNAA. For example, the treatment of PD patients with drugs such as L-dopa, amethyldopa and 5-hydroxytryptophan can be stabilized upon administration of the present compositions, particularly if a patient consumes these compositions on a regular basis.

The invention will be further illustrated by the following Examples, which are not intended to be limiting in any way.

Example 1 Effect of carbohydrate to protein ratio on plasma LNAA in healthy adults The effect one and three hours subsequent to consuming meals with varying carbohydrate to protein ratios on the plasma LNAA levels of healthy adult individuals was determined for carbohydrate to protein ratios ranging from 0.11:1 (high protein) to 16.7:1 (high carbohydrate). Both parallel designed experiments and crossover studies were employed to measure post-prandial LNAA levels. The subject's average age was approximately 67 years old with participation eligibility ranging from about 50 to 79 years old, similar to that of PD patients. Blood for plasma LNAA levels was drawn (time 0) just immediately prior to ingestion of a beverage or food of a specified carbohydrate to protein ratio (following a period of fasting) and at 1 hour and 3 hour post ingestion of the food. The levels of leucine, tyrosine, phenylalanine, tryptophan, valine and isoleucine were determined as well as the sum (total) of these LNAAs at times 0,1 and 3 hours.

A summary of the % change in levels of total LNAAs from baseline (time 0) values to either 1 hour or 3 hours after ingesting a drink having a carbohydrate to protein ratio of 4:1 to 8:1 can be found in Fig.1. The caloric content of these meals ranged from approximately 400 calories to approximately 600 calories and the PER for the protein was at least 2.5. As can be seen in Fig. 1, a meal having a carbohydrate to protein ratio of approximately 7:1 provided the most control over the variations in the levels of LNAA following ingestion of the meal. For comparison, the % change in the sum of LNAA at 1 hour and 3 hours following ingestion of a high protein meal (0.11:1 ratio) was +17 ± 13 and +48 ± 7, respectively. Following a high carbohydrate meal (16.7:1 ratio), the % change in the sum LNAA at 1 hour was -15 ± 2 and at 3 hours was -27 ± 27.

Example 2 Effects of fixed carbohydrate to protein ration of 7:1 with high protein (1.5:1) and high carbohydrate (30:1) taken for breakfast and lunch in Parkinsonian patients A randomized, double-blind crossover design was used to study patients (approximately 63.5 years old) with moderately severe Parkinson's Disease (approximately 13.4 years duration). Each subject received the 7:1 carbohydrate/protein (PER>2.5) drink, a high protein drink and a high carbohydrate drink for one week, each on separate weeks. L-dopa medication doses were unchanged for 1 month before the study and throughout the study. Subjects participated for a total of four weeks. Baseline parameters were established in week 1. They then randomly received each of the beverages for one week during weeks 2,3 and 4. At the end of each week, patients were observed in the Parkinson's Day Program for 11 hours. Hourly evaluations were done to assess plasma LNAA and levodopa concentrations in addition to the Unified Parkinson's Disease Rating Scale (UPDRS). Global assessments were also performed by the patients and physicians.

Patient diaries were completed each Thursday and Sunday.

The UPDRS was performed at each visit when the patient was on and was to reflect assessment at the patient's best level of function between visits. The percent of patients improving from baseline for UPDRS data were analyzed in each of the three treatment groups.

There were no statistically significant differences between treatments observed.

Global evaluations were done by the patient (5 point rating scale on helpfulness) and physician (7 point rating scale on total improvement) at the end of each treatment phase, in comparison to the first week of baseline. The 7:1 carbohydrate/protein beverage and high carbohydrate beverage were more helpful (p<0.0518) in comparison to the high protein beverage. Similarly, the physician's rating suggested (p>0.067) more improvement when the patients were taking the 7:1 carbohydrate/protein and high carbohydrate beverage when compared to the high protein beverage.

Part ΙΠ of the UPDRS was conducted hourly to assess motor skills during the day clinic visit. When time was included in the overall statistical model to consider the trends over the entire observation period, the 7:1 carbohydrate/protein beverage and the high carbohydrate beverage were shown to be significantly superior to the high protein beverage for change in total motor score. When analyzed hour by hour, there was a significant treatment effect in change from baseline for total score in the hourly motor examinations at 11:15 a.m. The 7:1 carbohydrate/protein beverage and the high carbohydrate beverage demonstrated a significant improvement over the high protein beverage. In addition, at 10:15 a.m. the 7:1 carbohydrate/protein beverage approached significant (p<0.08) when compared to the high protein beverage. Later that afternoon, at 4:15 p.m., again the 7:1 carbohydrate/protein beverage and high carbohydrate beverage approached statistical significant (p<0.07) when compared to the high protein beverage.

In each of the weeks of treatment on the three beverages, patients were asked to complete a 24 hour patient evaluation diary on Thursdays and Sundays of each week. Hour by horn·, they responded to the status of their motor function as ASLEEP; Good=good motor function; FAIR=able to move but troubled by involuntary or unintentional movements and POOR=able to move only slowly or not at all. The 7:1 carbohydrate/protein beverage and high carbohydrate beverage appeared to be more beneficial (p<0.06) to the patient than did the high protein beverage when evaluated by percent of good rating for when the patient was awake.

Fig. 2 shows that the 7:1 carbohydrate/protein beverage produced minimal fluctuations from baseline in the LNAA levels. As expected, the high protein beverage produced significant elevation in plasma LNAA levels and the high carbohydrate beverage produced levels of LNAAs consistently below baseline.

This study showed that the 7:1 carbohydrate/protein beverage and the high carbohydrate beverage demonstrate significant clinical benefit in several parameters assessing patient's subjective and objective criteria for improvement. Although not significantly different, the 7:1 carbohydrate/protein beverage did seem to trend in most assessments in favour of the 7:1 carbohydrate/protein beverage when compared to the high carbohydrate beverage.

Claims

Claims:

1. A nutritionally complete food product composition for administration to an individual to reduce fluctuations in plasma concentrations of large neutral amino acid levels, having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, wherein the protein has a protein efficiency ratio (PER) of greater than or equal to 2.5.

2. A nutritionally complete food product composition for use in repeated administrations to an individual over a predetermined period of time to sustain reduced fluctuations in plasma concentrations of large neutral amino acid levels for that predetermined period of time, having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, wherein the protein has a protein efficiency ratio (PER) of greater than or equal to 2.5.

3. A nutritionally complete food product composition for administration to an individual to reduce the variability of response to a large neutral amino acid drug in the individual, having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, wherein the protein has a protein efficiency ratio (PER) of greater than or equal to 2.5.

4. A composition according to any one of Claims 1-3, wherein the fluctuations are post-prandial fluctuations.

5. A composition according to any of Claims 1-4, wherein the ratio of carbohydrate to protein is approximately 7:1.

6. A composition according to any one of Claims 1-5, wherein the nutritionally complete food product is selected from a liquid formulation, a dehydrated powder capable of being reconstituted to form a liquid formulation, a soup, a dehydrated composition capable of being reconstituted to form a soup, a snack bar, an entree and a dessert.

7. A composition according to any one of Claims 2-6, when dependent on Claim 2, wherein the predetermined period of time is selected from 4 hours, 6 hours,

8. Hours, 12 hours, 18 hours, 24 hours, 48 hours and 1 week. 5 8. A composition according to any one of Claims 3-7, when dependent on Claim 3, wherein the drug is selected from L-dopa, amethyldopa and 5-hydroxytryptophan.

9. A composition according to any one of Claims 1-8, wherein the composition comprises approximately 400 to 600 calories.

10. 10. A composition according to any one of Claims 1-9, wherein the protein is selected from casein, caseinate, whey protein concentrate, lactalbumin, milk protein isolate, non-fat dry milk, egg white, 50:50 lactalbumin/soy protein isolate, 75:25 casein/soy protein isolate, 50:50 milk protein isolate/wheat protein and 50:50 15 lactalbumin/wheat protein.

11. Use of a nutritionally complete food product composition having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, wherein the protein has a protein efficiency ratio (PER) of greater than or equal to 2.5 in the manufacture of a medicament for 20 use in a method of reducing fluctuations in plasma concentrations of large neutral amino acid levels.

12. Use of a nutritionally complete food product composition having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, wherein the protein has a protein efficiency ratio (PER) 25 of greater than or equal to 2.5 in the manufacture of a medicament for use in a method of sustaining reduced fluctuations in plasma concentrations of large neutral amino acid levels for a predetermined period of time.

13. Use of a nutritionally complete food product composition 30 having a ratio of carbohydrate to protein of from greater than 6:1 to less than 8:1, wherein the protein has a protein efficiency ratio (PER) of greater than or equal to 2.5 in the manufacture of a medicament for use in a method of reducing the variability of response to a drug which is a large neutral amino acid in an individual.

14. Use according to any one of Claims 11-13, wherein the fluctuations are post-prandial fluctuations.

15. Use according to any one of Claims 11-14, wherein the ratio of carbohydrate to protein is approximately 7:1.

16. Use according to any one of Claims 11-15, wherein the nutritionally completed food product is selected from a liquid formulation, a dehydrated powder capable of being reconstituted to form a liquid formulation, a soup, a dehydrated composition capable of being reconstituted to form a soup, a snack bar, an entree and a dessert.

17. Use according to Claim 12, wherein the predetermined period of time is selected from 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, and 1 week.

18. Use according to Claim 13, wherein the drug is selected from L-dopa, α-methyldopa and 5-hydroxytryptophan.

19. A composition according to any one of Claims 1-3, substantially as hereinbefore described.

20. Use according to any one of Claims 11-13, substantially as hereinbefore described. .