DE1492910C3 - - Google Patents

Description

Growth factor ³ ) 30.0%

Fine cornmeal 3.75

³⁾ growth factor for poultry breeding, consisting of the extracts of Streptomyces fermentations, dried Streptomyces flours extracted with solvents soybean meal and tricalcium phosphate.

Of course, the antibiotic agents according to the invention can also be mixed with other feedstuffs be e.g. B. those, the smaller amounts, z. B. about 0.5 percent by weight, contain calcium.

The following comparative tests illustrate the potentiating effect of 3 - oxa - pentane-1,2,4,5 - tetracarboxylic acid, hereinafter referred to as 3-oxa acid for short, on tetracycline blood levels.

Experimental example 1

Ten 8 week old chicks (five males and five females) of the Vantress-White Rock-Cross breed were fed with a conventional feed of the type described above, which in addition 400 g oxytetracycline hydrochloride per ton and 3-oxapentane -1,2,4,5 - tetracarboxylic acid in one concentration of 0.5%, based on the total weight of the feed. A similar group became fed the same mixture of food and antibiotic, but not containing oxa acid. Blood samples were taken from all chicks 24 and 72 hours after the first antibiotic feeding taken to determine serum oxytetracycline levels. The results obtained are in the given in the table below.

substance

Average blood serum oxytetracycline levels

(y / ccm)

24 hours 72 hours

Potentiation effect (index)

24 hours

72 hours

Feed and water described above are given continuously. One group received a push dose orally of 250 mg oxytetracycline hydrochloride together with half the amount by weight of 3- Oxa-pentan- ' 1,2,4,5 - tetracarboxylic acid, while another group the two substances in weight ratio Got 1: 2, i.e. H. 250 mg oxytetracycline hydrochloride and 500 mg of 3-oxa acid. The same procedure was used for two other groups, but using of citric acid as a potentiating agent. Another group served as a control group. she received only the antibiotic (250 mg oxytetracycline hydrochloride). 2 and 6 hours after the antibiotic shock the oxytetracycline blood serum levels were determined by standard methods. The results are given in the table below:

Oxytetracycline · HCl 0.2280 0.2140 100 100

Oxytetracycline · HCl 0.2286 0.2679 103 125 + 3-oxa acid

They show that 3-oxa-pentane-1,2,4,5-tetracarboxylic acid the oxytetracycline blood serum level increased above that of the reference animals.

Experimental example 2

Thirty-five 11 week old female Vantress-White Rock-cross chickens were divided into five cages in groups of seven animals each. This one Animals were given acid throughout the experiment

control

Citric acid...
Citric acid...

Oxa acid

Oxa acid .......

Average
Oxytetracycline blood serum levels
(j // ccm)

2 hours 6 hours

0.990
1.219
1,788
2.816
6.724

0.794
0.566
0.875
0.867
2.266

Potentiation effect (index)

2 hours.

100
123
181
234
679

6 hours

They show that 3-oxa-pentane-1,2,4,5-tetracarboxylic acid too much higher blood levels of oxytetracycline leads than citric acid and that these blood levels are significantly higher than in the control group.

Experimental example 3

Experimental example 2 was carried out on an equal weight basis with chlorotetracycline and with tetracycline hydrochloride repeated in place of oxytetracycline. Both cases were essentially the same Results obtained as in experimental example 2.

Experimental example 4

Experimental Example 2 was made with fifty-four 12 week old Vantress-White Rock-Cross chickens repeated, which were divided into groups of six. The animals each received a mixture from 25 mg oxytetracycline with 80, 160 and 320 mg 3-oxapentane-1,2,4,5-tetracarboxylic acid. The on this The manner and results obtained with 320 mg of citric acid as a comparative substance are as follows Table compiled:

Potentiating agents

Dose mg

Water ecm Average oxytetracycline blood sera (y / ccm)

2 hours.

6 hours

Potentiation effect (index) 2 hours 6 hours

control
3-oxa acid ...
3-oxa acid ...
3-oxa acid ...
3-oxa acid ...
3-oxa acid ...
citric acid
citric acid

80 80 160. 160 320 320 320

5.0 5.0

10.0 5.0

10.0 5.0 5.0

10.0 0.322
0.478
0.299
0.397
0.591
0.544
0.289
0.325

0.119
0.259
0.148
0.220
0.170
0.219
0.156
0.143

100
148

93
123
184
169

90
101

100
218
124
184
143
184
131
120

They show that 3-oxa-pentane-1,2,4,5-tetracarboxylic acid is an effective potentiating agent for oxytetracycline and that with it in an amount of about ¹ Z ₄ . the amount of citric acid used, essentially the same results can be obtained after 6 hours have elapsed.

Experimental example 5

Experimental example 4 was with a larger dose of oxytetracycline hydrochloride, namely 500 mg repeated. There have also been mixtures containing tetracycline hydrochloride or chlortetracycline hydrochloride contained in doses of 25 and 500 mg. In all cases, the degree of potentiation substantially the same results as in Experimental Example 4 were obtained.

Experimental example 6

Seventy 6 week old chicks of the Vantress-White Rock-Cross breed were divided into seven groups of five male and five female chicks each subject to the conditions of test example 1, however, the agents administered contained different amounts of 3 - oxapentane -1,2,4,5 - tetracarboxylic acid. The results obtained are summarized in the table below.

Potentiating agents

None .......

3-oxa acid ...
3-oxa acid ...
3-oxa acid ...
3-oxa acid ...

concentration

0.01
0.1
1.0
2.0

Average
Oxytetracycline blood serum levels

(y / ccm)

24 hours

0.209
0.188
0.223
0.242
0.360

72 hours

0.221
0.245
0.240

Potentiation effect (index)

24 hours

100
90.1
106.6
115.9
179.9

72 hours

100
111
108.8

From this table it can be seen that 3-oxapentane-1,2,4,5-tetracarboxylic acid reaches its highest potentiating effect at a concentration of 2%.

Experimental example 7

For this experiment, 16 dogs that had not received any food for about 15 hours were given one Body weight of approximately 6.8 to 22.2 kg used. Seven of these dogs received the normal capsule with 250 mg oxytetracycline hydrochloride and glucosamine, while the remaining nine dogs take one capsule Received the 250 mg oxytetracycline hydrochloride and

ίο 250 mg 3 - oxapentane - 1,2,4,5 - tetracarboxylic acid contained. Blood samples were taken from the dogs for serum determination at 3 and 6 hours after administration taken. The results obtained in this way are shown in the table below:

substance

Oxytetracycline · HCl
+ Glucosamine

Oxytetracycline · HCl
+ 3-oxa acid

Average
Oxytetracycline blood serum levels
(y / ccm)

3 hours.

0.488
0.833

6 hours

0.304
0.518

Potentiation effect (index)

3 hours 6 hours

100
181

Experimental example 8

Sixty 8 week old chicks of the Vantress-White Rock-Cross breed were divided into six groups of five male and five female chicks were fed the aforementioned standard feed.

In three groups the feed contained oxytetracycline hydrochloride in amounts of 200, 500 and 1000 g / t and 3-oxa-pentane-1,2,4,5-tetracarboxylic acid in a concentration of 2.0 percent by weight, based on the total weight of the feed. In the other three groups, the diet contained the antibiotic alone, in the same doses. The chicks were done 24, 48 and 72 hours after the start of feeding Cardiac puncture Blood drawn to make blood serum determinations. The results are in the summarized in the following table:

Oxytetracycline Potentiating agents Average oxytetracycline 24 hours 48 hours : mj 72 hours Potentiation effect (index) 48 hours 72 hours concentration Blood serum level (y / c 0.117 0.127 0.099 100 100 . (g / t) none 0.808 0.342 .0.252 24 hours 100 100 200 none 0.586 0.697 0.677 100 100 100 500 none 0.198 0.273 0.214 100 215 216 , 1000 3-oxa acid 0.560 0.590 0.590 100 147 234 200 3-oxa acid 1.014 1,199 1,380 169 172 204 500. 3-oxa acid 181 1000 173

From the table above it can be seen that 60 contained. In all cases, the received

the 3-oxa acid in a concentration of 2% corresponds to the results in the order of the previous

Oxytetracycline blood levels in all three examined the experimental example at higher concentrations

Increased levels of oxytetracycline. obtained values comparable.

Experimental example 9

Experimental example 8 was repeated with the difference that the feed was oxytetracycline hydrochloride in concentrations of 50, 100 or 150 g / t test example 10

48 young Vantress-White Rock-Cross chicks were divided into groups of six males and six female chicks locked in cages. The animals

were then fed the standard basic feed, which in one group (twelve animals) was oxytetracycline in an amount of 400 g / t and 3-oxapentane-1,2,4,5-tetracarboxylic acid in the amount given below, while another group served as a control group. Another group received chow with chlortetracycline instead of oxytetracycline and 3-oxa acid, while the fourth group again served as a control group. Blood was drawn from the chicks 24 and 72 hours after the administration taken to determine blood serum levels. The results obtained in this way are shown in FIG compiled in the following table.

hydrochloride via oral tube. A second group received the same dose along with the same Amount of 3 - oxapentane - 1,2,4,5 - tetracarboxylic acid. A third group received neither antibiotics nor 3-oxa acid and served as a control group. A fourth group received only the 3-oxa acid. The animals were then caged for 18 hours after dosing of the metabolic dose and all urine output was collected. The animals received during this time no feed. However, they were given water ad libitum. The obtained in this way The results are shown in the table below:

Oxa acid Average 72 hours Concentration
tration Antibiotic- 100 antibiotic % Potentiation indices 198.5 none 24 hours 100 Oxytetracycline 2 100 190.5 Oxytetracycline none 241 Chlortetracycline. 2 100 Chlortetracycline 164.5

20th None Oral dose Average ■ Agents administered 3-oxa acid mg / kg ' excreted dose antibiotic % antibiotic - + 3-oxa acid 125 no activity 125 no activity 125 2.28 13.66

From the data in the table above it can be seen that 3-oxapentane-1,2,4,5-tetracarboxylic acid increases the oxytetracycline and chlortetracycline blood levels elevated.

Experimental example 11

A group of five albino rats received 125 mg / kg of o-desmethyl-o-deoxy-o-methylene-S-oxytetracycline-Aus It can be seen from the data in this table that 3-oxa acid at a dose of 125 mg / kg is a Much greater urinary excretion (about six times as large) of 6 - desmethyl - 6 - deoxy - 6 - methylene-5-oxytetracycline hydrochloride acts as if the antibiotic is administered alone.

409 618/162

Claims (1)

1 2 3 - oxapentane -1,2,4,5 - tetracarboxylic acid. Claim: An inert diluent, e.g. B. Starch, lactose, milk sugar or glucosamine Enterally applicable antibiotic agents can be applied for. It is also possible to veterinary medicine on the basis of tetra- 5 settlements in granulated or tablet form cyclin, oxytetracycline and chlortetracycline with pass, as well as in the form of aqueous suspensions, a potentiating agent, thereby creating elixirs, drops, etc. indicates that the potentiating agent ¹ The administration to pets, such as dogs, sheep, from 3 - oxapentane - 1,2,4,5 - tetracarboxylic acid chicks, turkeys, ducks, pigs and rabbits consists. 10 can also be used directly with the feed or drinking water take place, e.g. B. by using the inventive moderate composition, preferably in powder form, added to the feed. The antibiotic component of the feed can range from 50 g to about 1000 g per The subject of the invention are enterally applicable 15 tons of feed. The potency veterinary antibiotic must be included in an amount of at least 0.1 weight based on tetracycline, oxytetracycline and percent, based on the total weight of the feed, chlortetracycline with a potentiating agent. The antibiotic according to the invention are characterized in that the potentiating agent can be mixed with an animal feed component or agent of 3-oxapentane-1,2,4,5-tetracarboxylic acid 20 with the entire animal feed,
consists. With this potentiating agent, a suitable feed for admixture is achieved at significantly higher antibiotic blood levels than p. 6 in "Recommended Nutrient Allowances for with the agents previously used for this purpose, Poultry", June 1944, National Research Council of such as citric acid. Washington, D.C. Here feed-The production of the means according to the invention means the following composition is recommended: Approximately contained 3-oxa-pentane-1,2,4,5-tetracarboxylic acid 50 to 80% grain, z. B. ground grain or grain is described in U.S. Patent 3,128,287. By-products, molasses and other sugar by-products - The antibiotics mentioned do not just include the products; about 3 to 10% animal protein such as amphoteric tetracyclines such as tetracycline, chlortetfa fish meal, leftover meat and the like; about 5 to 30 weight cycline, oxytetracycline, 6 - desmethylchlorotetracycline, 30 percent vegetable protein, e.g. B. soy flour, peanut-6-deoxytetracycline, o-desmethyl-o-deoxy-tetracycline, cottonseed flour and the like and about 2 to about cyclin, 6-desmethyl-6-deoxy-7-bromo-tetracycline, 5% Minerals such as bone meal, lime, etc., o-desmethyl-ö-deoxy-o-methylene-S-oxytetracycline, together with additional vitamins such as thiamine, but also their acid salts such as riboflavin and nicotinic acid. The hydrochloride, hydrobromide, hydroiodide, sulfate, Ni-35 compositions according to the invention can be added to feed alone, phosphate, acetate, lactate, maleate, citrate, tartrate or together with other antibiotics and chemo- and ascorbate, as well as their salts with bases, such as the Therapeutic agents such as penicillin, bacitracin, sulfachin sodium, potassium, calcium, quaternary ammo-oxaline, phenylarsonic acid, hydroxyzine and oleandonium or ethylenediamine salts or the aluminum mycine can be added. Gluconate complex compounds and other grain 40 According to a specific embodiment of the A typical feed for poultry can make a typical feed for poultry through gisch usable salts of the antibiotics mentioned. Mix the following ingredients in the specified The potencies contained in the agent according to the invention are obtained in proportions:
The agent can also be used in the form of its bis-anhy- drids or its alkali metal or alkaline earth metal 45 Ground yellow corn meal 56,65 salts are used. Soy flour, 50% protein 33.75 The amount of potentiating agent can be internal alfalfa flour, 17% protein 2.00 fluctuate half a wide range. Usually stabilized animal fat 3.50 however, it is desirable that the dicalcium phosphate of the present invention be "2.00 Means at least half the amount by weight of 50 sodium chloride, iodized 0.50 Antibiotic to potentiators and preferred calcium carbonate 1.00 wise the same amount or an excess of the premix of trace minerals Contains potentiating agent. Optimal results and vitamins ¹ · ² ) - 0.60 _The premix of trace minerals makes up 0.05 Ge amount of 3 - oxa - pentane - 1,2,4,5 - tetracarboxylic _{acid, 55} percent by weight of the feed; the constituents contained therein, based on the weight of the tetracycline compound, parts are obtained, expressed in percent by weight of the premix. The use of the acid mentioned leads to manganese 24%; Iodine 0.48%; Iron 8.0%; Copper 0.8%; zinc too much for a given amount of antibiotic ₂ . ° j? ^% " ^nd ^ ^obalt ? ^{> 8} ° ^{/ o} ·. · _n ,, ~.. ■ 1 · 1 1 »11 1-11 y. ■ 1 1 · t_ · i_ · L j) The vitamin premix makes 0.55 percent by weight of the High blood levels higher than those previously achieved, _{from feed; the} components contained therein are or the same blood levels are given with a 60 following in percentages of the premix:
received a smaller amount of antibiotic. A preferred form of administration of the new vitamin A (10,000 I.U./g) ... 10.0% The composition consists of a powdered vitamin D ₃ (3000 ICE / g) 10.0% Mixture of the two main components, which in a choline chloride (25%) 35.25% hard or soft gelatin capsule included 65 nicotinic acid (80%) 0.55% is. This form of administration can be about 25 mg to DL-calcium pantothenate (45%) 10.0% about 500 mg of the desired tetracycline together riboflavin (8.1 g / kg) 0.39% with about half to 13 times the weight of vitamin B ₁₂ (130 mg / kg) 0.20%