GB2092001A - Pharmaceutical preparations comprising sodium fructose-1, 6-diphosphate for treatment of burn patients - Google Patents

Abstract

Pharmaceutical preparations, for intravenous or topical administration for the treatment of patients suffering from burns comprise as the active ingredient sodium fructose-1, 6-diphosphate. The compositions may contain conventional other ingredients, e.g. surfactants, antibiotics, antiseptics and humectants.

Description

SPECIFICATION Pharmaceutical preparations for the treatment of burn patients The present invention relates to pharmaceutical preparations having therapeutic action on burn patients.

It is well know that the systematic effects of burns derive mostly from the deprivation of the bloodstream of liquids having a protein content similar to that of plasma (Underhill, F.P. and Fisk, M.E. 1930, Amer. J. Physiol., 95,330), and from proteic hypercatabolism caused by stress and tissural injury (Wilmore, D.W. et al (1974), Am. Surg., 180,653).

Hence the treatment of burn patients requires a basic initial treatment (TPE) consisting of total parenteral nutrition (TPN) rich in calories and in proteins, integrated with suitable administration of albumin, plasma, whole blood and electrolytes (PE). However, the necessity of administering glucose and other nutrients by TPN to burn patients causes serious metabolic alterations, e.g. hyperazotemia and hyperglycemia (D.W. Wilmore: "Parenteral nutrition in burn patients" in "Current concepts in parenteral nutrition", edited by J.M. Greep, P.B. Soeters, R.l.C. Wesdorp, C.W.R. Phaf, J.E. Fischer (1977) pag. 227-239 Martinus Nijhoff-Medical Division, The Hague, Netherlands), due to hormonal disorders in the patient created by the stress factor.

These metabolic alterations badly affect the general state of burn patients, and above all the repair and restoration of the burnt tissues.

This in turn exposes the patient to the very grave risk of serious infection due to the slow regeneration of the burn tissues and in order to reduce such risks, it is of vital importance to accelerate to the utmost the normalization of the basic metabolism; in fact, the regeneration process of the burnt skin is basically dependent on this. Moreover, it is well known that these metabolic alterations cannot be resolved by the administration of insulin, which, among other things, has to be kept within strict limits to avoid other serious problems (as alteration of hyper- and hypoglycemic pitches, obstacle to lipolysis, insulinic rebound with a decrease in the prodcution of endogenous insulin, hyperglucagonemia, etc.). In addition, an excessive administration of insulin, by increasing the cellular hydration, handicaps the restoration and regeneration of burnt tissues.

It should be noted in particular that, up to the present time no therapeutic method has been found which is capable of accelerating the normalization process of burn patients' basic metabolism, and consequently acceleration of tissue regeneration, without incurring the problems outlined above.

The present invention on the other hand is based on the discovery that the problems induced in burn patients by the metabolic and structural alterations caused by the burns can be substantially reduced by the intravenous administration of the sodium salt of fructose-1,6-diphosphate (FDP) and that the intravenous administration of the sodium salt of FDP substantially protects the patient against the grave complications (mostly infective) that may set in when the 'burn disease' draws out.

Moreover it can be used without any inconveniences or complications.

The sodium salt of fructose-1, 6-diphosphate is well known in other pharmacological fields by virtue of its activity in cardiopathies, fatal suffering, secondary uterine inertia, gestosis, toxemic syndromes etc. However, ac- cording to the present invention the sodium salt of FDP is administered intraveneously at higher dosages than those previously used and at a higher speed of infusion.

It is therefore easy to see how the preparation according to the present invention may prove highly beneficial in all those cases where burn patients are concerned, when it is necessary to reduce to a substantial extent the complications setting in as a direct consequence of the extent and seriousness of burns.

Specifically therefore the present invention provides a pharmaceutical preparation comprising fructose-1, 6-diphosphate (FDP) in the form of its sodium salt, in lyophilic or microcrystalline powder form, in a parenternally administrable carrier or in a form suitable to be diluted in an aqueous solvent at the moment of use, and which can be intravenously administered to burn patients at a dosage rate (referring to the weight of laid sodium salt of FDP) not lower than 0.25 g/kg body weight per day.

This new application of the sodium salt of fructose-1, 6-diphosphate in burn cases is based on a previously unknown activity of FDP.

This surprising activity has been shown by trials carried out on rabbits, rats, guinea-pigs and Swiss mice, at the applicants' laboratories. Such tests stressed both the protective action resulting from pre-treatments by FDP (reducing animal mortality after experimental burns) and the therapeutic action of treatments by FDP (which were found to improve the general condition of animals after experimentally induced burns and to accelerate the repair of burnt tissue, and verified clinically by the Centro Ustioni - C.U. - Burnt Centre of S. Eugenio Hospital of Rome.

In this connection, those set out hereunder by way of illustrative example are the results of pharmacological tests carried out on Swiss mice, and the results of a series of clinical tests conducted on burn patients.

PHARMACOLOGICAL TESTS carried out on Swiss mice.

180 3 month old male Swiss mice, each weighing 19 i 1 gm. about 3 months old, divided in 6 groups of 30, were employed.

Treatment: X-ray irradiation: all the animals (groups 1, 2, 3, 4, 5, 6) were carefully irradiated by about 800 r of X-rays (250 KVp; 5 m A; distance of the irradiating source = 80 cm.;intensity 27 r/min.; exposure time 30').

FDP (groups 1, 3, 5): 150 mg/Kg body weight.

CHECK (groups 2, 4, 6): 10 ml/Kg body weight of physiological solution. FDP and CHECK treatments were administered intravenously (into cadual vein) in 8 seconds according to the following scheme: Groups 1 (FDP) and 2 (Check): subjected to three treatments respectively 24,14 and 1 hour before the X-rays irradiation.

Groups 3 (FDP) and 4 (Check): subjected to Xrays irradiation followed by a treatment per each day of observation.

Groups 5 (FDP) and 5 (Check): subjected to three treatments respectively 24,14 and 1 hour before the X-rays irradiation and after one treatment per each day of observation.

RESULTS: all mice of 'Check' groups (2, 4, 6,) died within 29 days from X-rays irradiation.

40 days after the X-rays irradiation, the survival rate in FDP groups was respectively of 8 mice (26.6 % in group 1), of 7 mice (23.3 % in group 3) and of 11 mice (36.6% in group 5).

TOTAL SURVIVAL: 26 mice (28.9%) in FDP groups (1, 3, 5). No mice (T2 = 15; p < 0.001) in CHECK groups (2, 4, 6).

PATIENTS. The test was conducted on 30 patients with burns covering from 10 to 40% of the body surface, with azotemic values ranging from 60 to 100 mg/100 ml, with glycemic values ranging from 1 25 to 300 mg/100 ml., and with no other complications associated with burns.

The patients were allotted to the two treatments compared according to a distribution pattern taking into account the succession of their hospitalization at the C.U. and the seriousness of their burns (which is fixed by preestablished criteria) so as to obtain two groups consisting each of 1 5 patients, as homogenous as possible in so far as age, grade and extent of burns as well as alteration of the metabolic picture (the latter determined mostly on the basis of the glycemic and azotemic values) are concerned. Under determined circumstances, moreover, (such as onset of grave infective complications, necessity for dialytic treatments, etc.) it is expected that patients discontinue the treatment and be replaced by others.

COMPARED TREATMENTS.

(1) TPE. It consists in the total parenteral nutrition (TPN) rich in calories and proteins, the composition of which varies only with respect to the patient's body weight and is integrated with administration of plasma, albumin, whole blood (administration which is proportional to the loss of flowing liquids suffered) and integrated as well with administration of electrolytes (calculated on the basis of their monitoring).

2) TPE + FDP. In addition to TPE itself, there are intravenously infused 0.25 g/kg body wheight of FDP, distributed over 3 daily administrations.

ASSESSED PARAMETERS.

In order to compare the effectiveness of the two treatments, there are taken into account both the azotemia normalization time (the number of the days during which azotemia kept above 50 mg/100 ml) and the glycemia normalization time (number of days during which glycemia kept above 120 mg/100 ml).

Blood samples for the azotemia and glycemia tests were taken every morning and sent over to the analysis laboratory after being marked by the relevant patient's code number. These parameters too were examined: EGC, X-rayschest, creatininemia, electrolytes, total and fractioned proteinemia, hemochrome, haematocrit value, analysis of blood gases, sensitivity test.

IT RESULTED THAT: by dividing the patients, two experimental groups sufficiently homogenous were formed.

They did not differ by age (age 32.73 i 7.15 and 35.40 + 6.31) " nor by the seriousness and extent of burns (percentage of body surface: 23.73 + 2.29 and 22.53 + 2.32) , nor by the basic azotemic values (80.5 + 2.3 and 81.2 + 2.4 mg/100 my)", nor by the basic glycemic values (210.3 + 12.9 and 205.7 + 11.6 mg/100 ml) ".

Even the azotemia normalization values ((44.7 + 1.0 and 44.9 + 0.9 mg/100 ml) 'and the giycemia normalization values (99.8 + 6.9 and 100.5 + 5.1 mg/100 ml) " coincided in both groups. FDP proved effective in diminishing both the azotemia normalization time (days 11.6 + 0.7 and 7.1 i 0.7; Mann-Whitney U-test : U = 23.5 p < 0.001)" and the glycemia normalization time (days 10.7 + 0.7 and 6.8 + 0.6; Mann-Whitney U-test = 27 p < 0.001) .

the first of average values (+ SE) in brackets refers to group 1 (treated by TPE), while the second refers to group 2 (treated by TPE + FDP).

From the above it results that the metabolic picture of the patients treated by FDP is much more quickly normalized. Furthermore, it should be noted that in both groups the azotmia normalization time (x; expressed in days) is significantly correlated with the glycemia normalization time (y): group 1 (TPE) y = 0.87 + 0.85 X, r = 0.90, p < 0.001 group 2 TPE + FDP) y = 0.90 + 0.83 x, r = 0.91 p < O.001 The coincidence of the two regression lines means that these two parameters may be advantageously used for determining the seriousness of the metabolic condition of burn patients.The trend of both the glycemic (y) and the azotemic (y) values is significantly (p < 0.001).correlated with the days of treatment (x) in both the patients' groups: 1) TPE group: (y=glycemia) y=211.73-9.66 xr=0.74 (y=azotemia) y= 80.88-2.9 Xr=0.85 2) TPE + FDP group: (y = glycemia)y = 214-15.43 X r = 0.76 (y=azoteiniia)y=76.8-4.4 X r = 76.8-4.4 X 0.77 Even by the trend of the other examined parameters and by clinical observations it can be seen that, in burn patients treated by FDP, the illness has a quicker and more favourable course. This bears out the fact that the processes of repairing burnt tissue are conditional on the normalization of the body metabolism on which depends the course of the illness as well as the gravity of related complications.

The pharmaceutical compositions of this invention comprise the sodium salt of fruc tose-l, 6-diphosphate in a parenterally administrable carrier, which will usually be an aqueous medium, or in a form suitable for dilution to prepare a parenterally administrable mixture of sodium fructose-l, 6-diphosphate in a suitable vehicle.As has already been indicated, the sodium fructose-l, 6-diphosphate will be administered intraveneously to burn patients at a daily dosage rate of at least 0.25 gm. per kg. of bodyweight and will be used in conjunction with conventional burn therapy including TPN, using protein and calorie rich infusion media, electrolyte adjustment using saline and/or other electrolyte solutions suited to the particular patients needs, albumin, plasma and whole blood infusions as may be required in any particular case. If desired and if convenient the sodium fructose-1, 6-diphosphate may be administered parentially in admixture with any of the foregoing media.Thus, included within the scope of this invention are parenterally adminstrable pharmaceutical compositions comprising sodium, 6-diphosphate in admixture with any of the following: 1. a parenterally adminstrable solution rich in glucose, protein or other nutrients, 2. a parenterally administrable electrolyte solution including saline solutions and electrolyte solutions containing cation(s) other than sodium and which are essential to maintain the electrolyte balance within the human body, 3. a parenterally adminstrable albumin or plasma, 4. whole blood.

As an alternative to intravenous administration sodium fructose-l, 6-diphosphate may be administered topically and accordingly the invention also includes topical compositions comprising sodium fructose-l, 6-diphosphate in a typically administrable carrier, e.g.

a salve or cream or ointment, or a solution, suspension, dispersion or emulsion in a liquid carrier optionally comprising additional ingredients such as surfactants, humectants, perfumes, colourants, antiseptics, antibiotics and other pharmaceutically active ingredients.

Claims (8)

1. A pharmaceutical preparation for parenteral administration to burn patients comprising the sodium salt of fructose-1, 6-diphosphate in a parenterally administrable vehicle or carrier.

2. A preparation according to claim 1, wherein the said salt is in microcrystalline or lyophilised powder form.

3. A preparation according to claim 1 or 2, wherein said vehicle is aqueous.

4. A preparation according to claim 3, which is parenterally administrable aqueous solution of the sodium salt of fructose-l, 6-diphosphate.

5. A preparation according to claim 1 or 2, wherein the vehicle comprises any of the following: 1) a parenterally administrable solution rich in glucose, protein or other nutrients, 2) a parenterally administrable electrolyte solution, 3) a parenterally administrable albumin or plasma, or 4) whole blood.

6. A pharmaceutical preparation for topical administration to burn patients comprising the sodium salt of fructose-l, 6-diphosphate in a topically administrable carrier.

7. A preparation according to claim 6, comprising said salt dispersed in a salve, cream or ointment base.

8. A preparation according to claim 6, comprising said salt in solution, suspension, dispersion or emulsion in a liquid carrier op tionally containing one or more of the follow- ing additional ingredients: surfactants, humectants, perfumes, colourants, antiseptics, antibiotics and other pharmaceutically active ingredients.