JPH0155249B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides fructose-1,6-diphosphate (FDP) with therapeutic activity for burn patients.
Concerning pharmacological preparations.

More specifically, the present invention relates to formulations of fructose-1,6-diphosphate sodium salt for intravenous administration that have a potent healing effect on metabolic disturbances and skin lesions resulting from burns.

Things that cause the systemic effects of burns include:
Bloodstream deprived of body fluids with protein content similar to plasma (FPUnderhill and MEFisk, Amer.J.
Physiol. 95, 330, 1930) and protein hypercatabolism due to stress and tissue damage (DW
Wilmore.al., Am.Surg., 180, 653, 1974).

Therefore, burn patients should receive basic treatment (TPE) of total parenteral intake (TPN) of caloric and protein-rich nutrients, along with appropriate administration of albumin, plasma, whole blood and electrolytes (PE). There is.

Burn patients with severe hormonal disturbances due to stress require the administration of large amounts of glucose and other nutrients on a TPN basis, thereby reducing hypernitemia and hyperglycemia. severe metabolic alterations characterized by (DW
Described in Wilmore's paper “Parenteral nutrition in burn patients.” This report was published in The Hague, Netherlands.
Marthnus, Nijhoff - JM of the Medical Division
Greep, PBSoeters, RICWedorp, CWR
Phaf and JEFischer (1977) in Concepts in Parenteral Nutrition, pp. 227-239 (1977). Here, "nitemia"
means the presence of urea and other nitrogenous substances in the blood, and "glycemia" means the presence of glucose in the blood (Dorland Medical Dictionary, Hirokawa Shoten). Then, “hypernitemia”
and "hyperglycemia" refer to high levels of nitrogenous substances and glucose, respectively.

These metabolic alterations have a negative impact on the general condition of burn patients, especially on the recovery and healing process of burnt tissues. If burn skin regenerates too slowly, the patient may
In particular, it exposes the person to a very serious risk of infection. In order to reduce such risks,
It is extremely important to promote normalization of the patient's metabolism as much as possible. That is, the regeneration process of burnt skin basically depends on this. Insulin administration is one of the other ways to eliminate these modulations, but it is also possible to modify hyper- and hypoglycemic pitches caused by insulin administration, impede lipolysis, and reduce endogenous insulin. In order to avoid serious disadvantages such as insulin rebound, hyperglucagonism, etc. due to decreased production, its administration must be maintained within certain limits. Therefore, it is known that no resolving effect can be obtained by administering insulin. Moreover, excessive administration of insulin will increase cell hydration, thus being detrimental to the recovery and regeneration of burn tissue.

So far, without the above-mentioned defects,
It should be particularly noted that no treatment method has been found that can promote the normalization process of the metabolic profile of burn patients, ie, the regeneration of burn skin.

The present invention provides fructose-1,
By using the sodium salt of 6-diphosphate, the harm caused by the metabolic and structural alterations caused by burns is substantially reduced and, therefore, the serious complications that can occur during prolonged "burn sickness" (mostly It offers a surprising solution to protect patients from infectious diseases.

The sodium salt of fructose-1,6-diphosphate is known in other pharmacological fields because of its activity in heart disease, fetal distress, secondary uterine incompetence, pregnancy toxicity, toxemia syndrome, etc. ,
This substance does not cause any inconvenience or complications.

However, it must be noted that the products of the present invention are administered intravenously at higher doses and at faster infusion rates than previously known and used for the above-mentioned activities. Therefore, how advantageous is the formulation of the invention in all cases involving burn patients, where there is a need to substantially reduce the complications arising as a direct result of the extent and severity of burns? You will understand.

A specific subject of the invention is therefore fructose-1,6-diphosphate (FDP) in the form of its sodium salt, in lyophilized form or in microcrystalline powder.
pharmacological preparations, which must be diluted in an aqueous solvent (or otherwise prepared in advance with an aqueous solution of the sodium salt) before use.
For burn patients, the drug is administered intravenously at a dose of 0.25 g or more per 1 kg of body weight (refers to the content of fructose-1,6-diphosphate sodium salt).

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

This surprising activity was demonstrated in pharmacological studies carried out on rabbits, rats, guinea pigs and Swiss mice at the Biomedica Foscama laboratory. The study demonstrated the protective effect of pre-administration of FDP (reducing animal mortality after experimental burns) and the therapeutic effect of treatment with FDP (improving the general condition of burnt animals and favoring the healing process of burnt skin). Both of these were confirmed.

This novel activity of FDP was found by the pharmacological studies carried out on animals, but it was also substantiated by clinical tests (CentroUstioni (CU), S.Eugenio Hospital for Burns, Rome). Center).

In this connection, listed below as an illustrative example of the invention are the results of pharmacological tests carried out on Swiss mice, and the results of a series of clinical trials carried out on burn patients.

Pharmacological studies on Swiss mice Male Swiss mice, approximately 3 months old and weighing 19±1g
The 180 animals were divided into 6 groups of 30 animals each.

Treatment: X-ray irradiation. All animals (groups 1, 2,
3, 4, 5, 6) were carefully irradiated with X-rays at approximately 800 r (250 KVp; 5 mA; distance from the irradiation source = 80
cm; intensity 27 r/min; irradiation time 30′). FDP (Groups 1, 3, 5): 150mg/Kg body weight. Control (Groups 2, 4, 6): Physiological solution 10ml/Kg body weight. FDP and control were administered intravenously (tail vein) in 8 seconds according to the following schedule.

Groups 1 (FDP) and 2 (control): treated three times 24, 14 and 1 hour before X-ray irradiation, respectively. Groups 3 (FDP) and 4 (control): after X-ray irradiation;
Treatment was performed once on each observation day.

Groups 5 (FDP) and 6 (control): treated three times 24, 14 and 1 hour before X-ray irradiation, respectively, and once on each observation day after irradiation.

Results: All mice in the control group (2, 4, 6) died within 29 days after X-ray irradiation.

The survival rate within the FDP group after 40 days of X-ray irradiation was
They were 8 (group 126.6%), 7 (group 323.3%) and 11 (group 536.6%), respectively.

Overall survival: 26 in FDP group (1, 3, 5)
(28.9%). No mice survived in control groups (2, 4, 6) (τ ² =15; p<0.001).

Clinical Trials Tests were conducted on 30 patients with burns covering 10-40% of their body surface. The patient's axemia value (blood concentration of nitrogenous substances) ranges from 60 to 100 mg/100ml, and his glycemia value (blood glucose concentration) is 125.
~300mg/100ml and there were no burn related complications.

Patients were divided into two comparison treatment groups according to the distribution pattern, taking into account the patient's length of stay in the CU and the severity of the burn (determined by previously established criteria). Two groups of 15 patients each were tested as far as age, extent and extent of the burns, and modulation of the surrogate images (which were determined largely on the basis of blood glucose and axemia values). I tried to make it as uniform as possible. Furthermore, it was anticipated that under defined circumstances (e.g. development of significant infectious complications, need for dialysis treatment, etc.) patients would have to discontinue treatment or be transferred to other patients.

Comparative treatments: 1) TPE. This consists of total parenteral intake (TPN) of calorie- and protein-rich nutrients, the composition of which varies only depending on the patient's weight, along with plasma, albumin, and whole blood (to account for fluid loss). Administer proportional doses) and electrolytes (calculated based on monitors).

2) TPE+FDP. In addition to TPE, per 1 kg of body weight
Inject 0.25 g of FDP intravenously in three divided doses per day.

Parameters evaluated: In order to compare the effectiveness of the two treatments, the axemia normalization time (azotemia values of 50 mg/100 ml in a row)
(the number of days in which the blood glucose level was above 120mg/100ml) and the time to normalization of glycemia (the number of days in which the blood sugar level remained above 120mg/100ml) should be taken into consideration. Blood samples for axenemia and glycemia tests were collected every morning, labeled with the patient's code number, and sent to the analytical laboratory. The following parameters were also tested: EGC, chest x-ray, creatininemia, total and differential proteinemia, hemochrome, hematocrit levels, blood gas analysis, and sensitivity tests.

Results: By separating the patients, two sufficiently homogeneous experimental groups were created. Both groups were significantly lower in age (age: 32.73±7.15 and 35.40±6.31) and burn severity and extent (percentage of body surface: 23.73±
2.29 and 22.53 ± 2.32), and basal azotemia (80.5
There was no difference in basal glycemic values (210.3 ± 12.9 and 205.7 ± 11.6 mg/100 ml).

Nitemia normalization value (44.7±1.0 and 44.9±0.9mg/
100ml) and normalized glycemic values (99.8±6.9 and 100.5±
5.1mg/100ml) was consistent in both groups.

(The first value of the mean value (+SE) in parentheses refers to Group 1 (treatment with TPE), and the second value refers to group 2 (treatment with TPE + FDP). The same applies hereafter. ) FDP is the time to normalization of axemia (days, 11.6±0.7
and 7.1±0.7; Mann-Whitney U-test,
U = 23.5p < 0.001) and glycemia normalization time (days,
10.7±0.7 and 6.8±0.6; Mann-Whitney U-
test, it was found to be effective in reducing both U=27p<0.001).

From the above it follows that the metabolic profile of patients treated with FDP normalizes much more quickly. Furthermore, it must be noted that in both groups, the time to normalization of axemia (X, expressed in days) is significantly correlated with the time to normalization of glycemia (Y). : Group 1 (TPE) Y=0.87+0.85X r=0.90, p<0.001 Group 2 (TPE+FDP) Y=0.90+0.83X r=0.91, p<0.001 The agreement between the two regression curves is due to the fact that these two parameters This means that it can be advantageously used to determine the degree of severity of the metabolic state of burn patients.

The trends in both the glycemia level Y and the axenemia level Y were determined by the number of days of treatment (X) in both groups of patients.
There is a significant (p<0.001) correlation with: 1) TPE group: (Y=glycemia) Y=211.73-9.66X r=0.74 (Y=nitemia) Y=80.88-2.9X r=0.85 2) TPE + FDP group: (Y = Glycemia) Y = 214-15.43X r = 0.76 (Y = Nitemia) Y = 76.8-4.4X r = 0.77 Trends in values of other tested parameters and clinical observations The results show that the disease progresses more quickly and favorably in burn patients treated with FDP. This proves that the recovery process of burnt tissue is based on the normalization of metabolism, and that the course of the disease and the severity of associated complications depend on it.

Although the invention has been described with respect to a particular specific application, it will be understood that variations and modifications may be made therefrom provided that they do not depart from the scope of the invention.

Claims (1)

[Scope of Claims] 1. A therapeutic agent for burn patients comprising fructose-1,6-diphosphate sodium salt as an essential component. 2 Microcrystalline or lyophilic powdered fructose
The therapeutic agent according to paragraph 1, consisting of 1,6-diphosphate sodium salt and a solvent for intravenous injection. 3. The therapeutic agent according to item 1, which is an aqueous solution of fructose-1,6-diphosphate sodium salt. 4. Daily dose is at least 0.25g/Kg (body weight)
The therapeutic agent according to any one of Items 1 to 3, which is adjusted to satisfy the following conditions. 5. The therapeutic agent according to any one of Items 1 to 3 for local administration. 6. The therapeutic agent according to any one of Items 1 to 4 for systemic administration.