GB2157561A

GB2157561A - An injectable solution especially for treating ketosis

Info

Publication number: GB2157561A
Application number: GB08507176A
Authority: GB
Inventors: Karoly Magyar; Ferenc Simon; Attila Misley; Jozsef Kelemen; Hedvig Szauder; Peter Sarkozi; Zsuzsa Mora; Attila Mandi
Original assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Current assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Priority date: 1984-03-20
Filing date: 1985-03-20
Publication date: 1985-10-30
Also published as: JPS60260510A; FR2561522A1; HU191598B; GB2157561B; DE3505572A1; HUT37035A; GB8507176D0; DE3505572C2; BE901959A; FR2561522B1

Abstract

The injectable solution comprises of 1 to 50 percent by weight of glucose, 0.002 to 2 percent by weight of nicotinic acid, 0 to 10 percent by weight of additive(s) and 38 to 98.998 percent by weight of water. The injectable solution of the invention can be used for treating serious cases of ketosis and fatty liver syndrome, furthermore septic processes, states of reconvalescence, prolonged anorexia and insufficient carbohydrate supply as well as for feeding the animals parenterally. The additive(s) may be sodium formaldehyde bisulfite, thioglycerol, alkali or alkali earth metal halogenides, vitamins B6 or B12 and/or amino acids.

Description

SPECIFICATION An Injectable Solution Especially for Treating Ketosis and a Process for the Preparation Thereof The invention relates to an injectable solution especially for treating ketosis and a process for the preparation thereof.

In cattle-keeping, the disease of ketosis affecting cows is more and more frequent as milk production becomes higher. The ketosis can be characterized by a degeneration of liver and the appearance of a fatty liver. The cause of this illness is that for about 2 months before calving the cows are fed with a fodder having too high protein and low carbohydrate content resulting in troubles in the metabolism at the time of calving. Due to the developed lactation ketosis, milk production is decreased. Especially the Holstein Friesian species and their interbred offsprings are inclined to these troubles of metabolism.

In the moderate cases of ketosis, daze or paralysis develops while in the serious cases of ketosis the fat reserves of the cow get liberated, lipid appears in the blood and deposits in the liver, leading to an irreversible degeneration of liver and usually to the death of the animal.

Extremely high economical damage is caused by ketosis in cattle keeping since just the cows giving very much milk perish. In addition to the direct material losses it is a genetic damage, too, since just the cows giving high quantities of milk are not able to transmit this property.

At present there is no pharmaceutical composition available for the efficient treatment of the serious cases of ketosis.

Now it has been found that these serious cases can be efficiently treated by an injectable solution comprising 1 to 50 per cent by weight of glucose, 0.002 to 2 per cent by weight of nicotinic acid, 0 to 10 per cent by weight of additive(s) and 38 to 98.998 per cent by weight of water.

The injectable solution of the invention may contain one or more additives such as stabilizers, e.g.

sodium formaldehyde bisulfite, thioglycerol or a mixture thereof; inorganic salts, e.g. alkali or alkali earth metal halogenids such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium iodide or a mixture of several inorganic salts; vitamins, e.g. vitamin B6, B12 or a mixture thereof; amino acids or derivatives thereof, e.g. L-lysine hydrochloride, DL-methionine, L-valine, L-cysteine hydrochloride, sodium glutamate or a mixture of several amino acids and/or amino acid derivatives.

The injectable solution of the invention comprises preferably 20 per cent by weight of glucose, 0.06 per cent by weight of nicotinic acid and 79.94 per cent by weight of water.

The injectable solution of the invention is prepared by dissolving 1 to 50 per cent by weight ofglucose, 0.002 to 2 per cent by weight of nicotinic acid and 0 to 10 per cent by weight of additive(s) in 38 to 98.998 per cent by weight of water.

The water used for dissolving the solid constituents is, in general, distilled water but physiologic saline can be employed, too.

The solid constituents can be separately dissolved in small portions of water, then the aqueous solutions are combined and the concentration required is adjusted by the addition of further water.

Alternatively, the solid components, i.e. glucose, nicotinic acid and additive(s), are blended, the powder mixture is optionally ground, then dissolved in water or saline.

The solution obtained is filled into ampoules or bottles. Sterilization is performed either before or after filling the solution into ampoules or bottles.

If desired, the above powder mixture is filled into powder ampoules, and it is dissolved directly before administration.

Surprisingly, a synergistic effect has been established in the treatment with glucose and nicotinic acid.

This synergism was studied on sheep as a model on the basis of the protection against liver injuries induced experimentally.

Four groups of animals, each consisting of 5 ewe lambs of merino type weighing 30+2 kg, were subjected to the examinations. A specimen was taken from the blood of each animal, then the sheep were treated intraruminally with the following solutions causing liver injury: - a mixture of paraffin oil and carbon tetrachloride in a voluníe ratio of 1 to 1; dosis: 0.24 ml/kg body weight; - 10 per cent aqueous thioacetamide; dosis: 0.12 mg/kg body weight; - 2 per cent aqueous allylalcohol; dosis: 0.2 ml/kg body weight.

The above agents were given directly one after the other. In this way, various injuries of liver were developed but the life of the sheep was not endangered.

After the day of this treatment (day zero), the animals were treated for 4 days (from day 1 to day 4), twice daily, with 50 ml of the solution to be tested. This solution was administered in infusion.

Group I of the animals was treated with physiologic saline, Group II with 20 per cent glucose in physiologic saline, Group Ill with 0.06 per cent nicotinic acid in physiologic saline and Group IV with physiologic saline containing 20 per cent by weight of glucose and 0.06 per cent by weight of nicotinic acid.

Every day, before the first treatment, a specimen was taken from the blood of each animal. Although the treatment was finished on day 4, specimen was taken from the blood of each animal forfurther 5 days (from day 5 to day 9). The activity of the enzymes aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) was determined. From the activity values of the animals, the average was calculated for each group.

The injury of liver is indicated by an increase in the activity of these enzymes. If the normal enzyme activities (i.e. the activity values existing before the liver injuries) are restored, then these injuries are stopped. The results obtained are summarized in Tables I and II.

TABLE I Activity of the Enzyme Aspartate Aminotransferase (AST) Activity of AST in Activity Unit Per Litre on Day Group of Animal 0 1 2 3 4 7 9 I (control) 41.6 308 370.5 251.7 187 147 87 II (glucose) 38.0 283 336 231 177 113 71 Ill (nicotinicacid) 36.0 276 324 239 172 108 63 IV (solution ofthe invention) 39.0 293 244 168 103 61 43 TABLE II Activity of the Enzyme Lactate Dehydrogenase (LDH) Activity of LDH in Activity Unit Per Litre on Day Group of Animal 0 1 2 3 4 7 9 I (control) 603 2828 4532 4179 3442 1892 1010 II (glucose) 645 2734 4648 3450 3058 1527 1090 Ill (nicotinicacid) 629 2796 4461 3365 2968 1453 991 IV (solution ofthe invention) 618 2696 2725 2100 1415 867 636 From Table lit can be seen that in the control group (Group I) the activity of AST increased until day 2, then gradually decreased, but the initial value was not restored on day 9.

The same changes of activity were observed in Groups II and Ill.

in Group IV, where the solution according to the invention was used, a decrease of activity could be observed already on day 2, and this decrease was continuous until day 9 when the initial value of activity was obtained.

The activity of enzyme LDH has shown similar changes.

The data of Tables I and II indicate clearly that the enzyme activities tested are not influenced by using separately glucose or nicotinic acid, thus, no liver protection is exerted. However, a combination of these agents shows a considerable liver protection.

The injectable solution according to the invention is administered into the artery of cows preferably by infusion, in general, 1 to 3 times daily, depending on the severity of the illness. In addition to the serious cases of ketosis and fatty liver syndrome, the injectable solution of the invention can be used for treating septic processes, states of reconvalescence, prolonged anorexia and insufficient carbohydrate supply as well as for feeding the animals parenterally.

The invention is further elucidated by means of the following Examples.

EXAMPLE 1 A solution comprising the following constituents is prepared: glucose 100.0000 g sodium chloride 13.0000 g potassium chloride 5.0000 g calcium chloride 4.2000 g magnesium chloride 1.2000 g potassium iodide 0.0010 g L-lysine hydrochloride 0.0900 g DL-methionine 0.0450 g L-valine 0.0270 g L-cysteine hydrochloride 0.0065 g sodium glutamate 0.0600 g vitamin B6 0.1000 g vitamin B12 0.0001 g nicotinic acid 0.3000 g sodium formaldehyde bisulfite 1.0000 g distilled water to make 500.0000 g The constituents listed are dissolved in distilled water, then the quantity of the solution obtained is adjusted to 500 g with further distilled water. The solution is filtered through a filter having a pore size of 0.45 pom, filled into an infusion bottle under nitrogen, the bottle is sealed and sterilized at 110 C for 20 minutes.

EXAMPLE 2 Example 1 is repeated with the difference that 5 g of glucose and 10 g of nicotinic acid are employed; EXAMPLE 3 Example 1 is repeated with the difference that 250 g of glucose and 0.01 g of nicotinic acid are employed.

Claims

1. An injectable solution especially for treating ketosis comprising 1 to 50 per cent by weight of glucose, 0.002 to 2 per cent by weight of nicotinic acid, 0 to 10 per cent by weight of additive(s) and 38 to 98.998 per cent by weight of water.

2. An injectable solution as claimed in claim 1, comprising 20 per cent by weight of glucose, 0.06 per cent by weight of nicotinic acid and 79.94 per cent by weight of water.

3. A process for the preparation of an injectable solution especially for treating ketosis, in which 1 to 50 per cent by weight of glucose, 0.002 to 2 per cent by weight of nicotinic acid and 0 to 10 per cent by weight of additive(s) are dissolved in 38 to 98.998 per cent by weight of water.

4. A process as claimed in claim 3, in which a mixture of 1 to 50 per cent by weight of glucose, 0.002 to 2 per cent by weight of nicotinic acid and 0 to 10 per cent by weight of additive(s) is dissolved in 38 to 98.998 per cent by weight of water directly before administration.

5. A solution as claimed in claim 1 substantially as hereinbefore described in Example 1 or Example 2 or in connection with the tests whose results are shown in Tables 1 and 2.

6. A method as claimed in claim 3, substantially as hereinbefore described in connection with the tests whose results are given in Tables 1 and 2.

7. A powder composition for making up into an injectable solution, which composition comprises 1 to 50 parts by weight of glucose, 0.002 and 2 parts by weight of nicotinic acid and 0 to 10 parts by weight of one or more soluble additives, optionally together with instructions for dissolving said composition in 38 to 98.998 parts by weight of water.