DE3645343C2 - Low dosage interferon administration to warm blooded vertebrates - Google Patents

Abstract

A biologically active interferon is administered to warm-blooded vertebrates in a daily dosage of at most about 5 IU/lb body wt. Cpd. is pref. of human interferon alpha, orally at a daily dosage of 0.1-1.5 IU/lb. for 3 consecutive days. The administration can be to bovine, porcine, caprine, ovine, avian feline, canine and equine animals, as well as humans.

Description

The invention relates to Use of α-interferon in low doses Influencing the appetite and effectiveness of the feed exploitation in warm-blooded vertebrates.

"Interferon" is a general term that refers to a group  glycoproteins and vertebrate proteins, which are known to show different biological effects, e.g. B. antivirus, antiproliferative and immune modulations effects on animal species from which these substances are obtained can be. The following definition of interferon is by an international committee for the creation of a Systems for proper nomenclature of interferons accepted: "To be considered interferon, a factor must be a protein that is virus-unspecific, antiviral effects at least in homologous cells involving cellular metabolic processes both which has both RNA and protein synthesis. "; cf. Journal of Interferon Research, 1, p. VI (1980).

Since the first reports of Isaac and Interferon Lindeman (See, Proc. Roy. Soc. London (Ser. B), Vol. 147, Pp. 258 ff (1957) and U.S. Patent 3,699,222) is Interferon on the all over the world the goal of intensive research be. There are a myriad of publications about that  Synthesis of interferon; M. Wilkinson and A.G. Morris, Interferon and the Immune System 1: Induction of Interferon by Stimulation of the Immune System, Interferons: From Molecular Biology to Clinical Application, ed. D. C. Burke and A.G. Morris, Cambridge Univ. Press, 1983, pp. 149-179; P.I. Marcus, chap. 10, Interferon Induction by Virus, Inter ferons and Their Applications, ed. P. E. Came and W. A. Carter, Springer Verlag, (Handbook of Experimental Pharma cology V. 71) 1984, pp. 205-232; proposed molecular Characteristics; P. B. Sehgal, How Many Human Interferons Are There? Interferon 1982, ed. I. Gresser, Academic Press, 1982, pp. 1-22; J. Collins, Structure and Expression of the Human Interferon Genes, Interferons: From Molecular Biology to Clinical Application, ed. D. C. Burke and A. G. Morris, Cambridge Univ. Press, 1983, pp. 35-65; K. C. Zoon and R. Wetzel, chap. 5, Comparative Structures of Mammalian Inter ferons, 1a: Interferons and Their Applications, ed. P.E. Came and W. A. Carter, Springer Verlag, (Handbook of Expe rimental Pharmcology V. 71) 1984, pp. 79-100; clinical Applications; M. Crimea, chap. 1, Interferons and Their Appli cations: Past, Present, and Future, Interferons and Their Applications, ed. P.E. Came and W.A. Carter, Springer Verlag, (Handbook of Experimental Pharmacology V. 71) 1984; S. B. Greenberg and M. W. Harmon, chap. 21, Clinical Use of Interferons: Localized Applications in Viral Diseases, Ibid. Pp. 433-453; proposed mechanism of anti-tumor, Antivirus and immune system effects. G.M. Scott, The Antiviral Effects of Interferon, From Molecular Biology to Clinical Application, ed. D. C. Burke and A. G. Morris, Cambridge Univ. Press, 1983, pp. 279-311; M. McMahon and I. M. Kerr, The Biochemistry of the Antiviral State, Ibid. Pp. 89-108; J. S. Malpas, The Antitumor Effects of Interferon, Ibid. Pp. 313-327; J. Taylor-Papadimitrion, The Effects of Inter feron on the Growth and Function of Normal and Malignant Cells, Ibid. Pp. 109-147.  

Because of the intensity and the different origins of the Research on interferon and its properties as well as uses there is a significant lack of one consistency in such aspects as classification of interferon types. There are also numerous, occasionally contradictory theories about how the Inter works ferons in eliciting clinical effects. The following short summary of the current state of knowledge about Interferon will help in understanding the present invention help.

Although originally isolated from poultry cells (Allantoic Chicken cells) is the interferon formation in cells classes of vertebrates including mammals, Amphibians and reptiles have been observed. The interferon Vertebrate cell formation rarely occurs spontaneously, but is often used easily in the treatment of cells (in vivo or in vitro) with a variety of substances "induces" which viruses, nucleic acids (including those from viruses and synthetic polynucleotides), Lipopolysaccharides and various antigens and mitogens lock in.

Interferons are generally classified according to the types of sub punch-producing cells (e.g. human, Mouse or bovine), still according to the cell type concerned (e.g. Leukocytes, lymphoblastoids, fibroblasts) and occasionally of the type responsible for interferon production inducing material (e.g. virus, immune). interferon is superficial by some scientists Induction type has been classified as Type I or Type II, the first class being virus and nucleic acid induced Interferon and the second class that is formed as a lymphokine  Material by induction by antigens and mitogens closes. Recently the international committee classifies that complies with the proper nomenclature system for Inter feron deals with interferon by type based on the Antigen specificity. In this newer classification uses the terms alpha (α), beta (β) and gamma (γ), the former names of leukocyte, fibroblast and Correspond to type II (immune) interferons. Alpha and beta interferons are usually acid stable and correspond to those formerly referred to as Type I interferons. Gamma interferons are usually acid labile and correspond those formerly called Type II interferons. The Recommendations of the international committee's nomenclature only human and mouse interferons. Journal of Inter feron Research, 1, p. VI (1980).

Determining the precise molecular structure of the interferon was not for some time with the means of the prior art possible. In the years after interferon first appeared as a protein was well characterized on the basis of his Deactivation by trypsin were attempts at its rei inclination and unambiguous characterization impossible because of its high specific activity and its apparent Heterogeneity. Today, for Interferon, some precision is involved determination of the molecular structure has been achieved, cf. P. B. Sehgal, op. Cit .; J. Collins, op. Cit .; K. C. Zoon and R. Wetzel, op. Cit.

In its earliest applications, interferon was exclusive used as an antiviral. The most successful clinical therapeutic application to date has been used in the treatment of Viral diseases instead. However, it was found that exogenous Interferon in various metastatic disorders sometimes can cause regression or remission. An over  view of current clinical trials with interferon as a therapeutic antiviral and antiproliferative medium to early 1983 is in The Biology of the Interferon System 1983, Proceedings of the Second International TNO Meeting on the Biology of the Interferon System, Rotterdam, The Netherlands, 18.-22. April 1983, and Antiviral Research, March 1983, Special Abstract Issue, Elsevier / North-Holland Biomedical Press, Netherlands, ent hold.

The clinical tool of choice for this work is human leukocyte interferon, on a "large scale" provided by procedures that the collection and purification of large amounts of leukocytes from human centrifuged Blood, induction with viruses and isolation from culture include media. The need for human interferon Origin lies in the long-standing conclusion establishes that interferon is "species-specific", i.e. H. biological is effective in vivo only in those species that are homologous to the production cells.

In the work described above, interferon was found administered terally, d. H. intramuscularly and intradermally, whereby about some successful topical and intranasal applications has been reported. It is rarely administered intravenously been because of significant adverse effects that "Impurities" in raw and even in highly purified Isolates are attributed. Applicants' invention according to US Pat. No. 4,462,985 and according to PCT application PCT / US 81/01103, filed on August 18, 1981 and published on March 4 1982 - to the content of which reference is made here the use of interferon from heterological species and also oral administration.  

Prior to these releases, it has no reports of therapeutically successful oral administrations of Inter given feron. This is in line with the widespread Considers that interferon is in the vicinity of the digestive system tract of animals is not stable.

In addition to use in the antivirus and antitumor therapy has recently been found that interferon is also immuno shows modulatory effects, both immunopotent decorative as well as immunosuppressive effects. B. Lebleu and J. Content, Mechanisms of Interferon Action: Biochemical and Genetic Approaches, Interferon 1982, ed. I. Gresser, Academic Press, 1982, pp. 47-94; M. Moore, Interferon and the Immune System, 2: Effect of IFN on the Immune System, Interferons: From Molecular Biology to Clinical Application, Ed. D. C. Burke and A. G. Morris, Cambridge Univ. Press, 1983, pp. 181-209; H. Smith-Johannsen, Y-T Hou, X-T Liu, and Y-H Tan, chap. 6, Regulatory Control of Interferon Synthesis and Action, Interferons and Their Applications, ed. P.E. Came and W. A. Carter, Springer Verlag, (Handbook of Expe rimental Pharmacology V. 71) 1984, pp. 101-135; J.L. Raylor, J. L Sabram, and S.E. Grossberg, chap. 9, The Cellular Effects of Interferon, Ibid. Pp. 169-204; J. M. Zarling, Effects of Interferon and Its Inducers on Leukocytes and Their Immuno logic functions, Ibid. Pp. 403-431; R. Ravel, The Interferon System in Man: Nature of the Interferon Molecules and Mode of Action, Antiviral Drugs and Interferon: The Molecular Basics of Their Activity, ed. Y. Becker, Martinus Nÿhoff Pub., 1984 pp. 357-433.

Furthermore, "new" biological effects for exogenous and endogenous interferon detected. K. Berg, M. Hokland, and I. Heron, Biological Activities of Pure  HuIFN-Alpha Species, Interferon, Properties, Mode of Action, Production, Clinical Application, ed. K. Munk and H. Kirchner, (Contributions to Oncology V. 11) pp. 118-126; S. Pestka et al., The Specific Molecular Activities of Inter ferons Differ for Antiviral, Antiproliferative and Natural Killer Cell Activities, The Biology of the Interferon System, 1983, ed. E. DeMaeyer and H. Schellekens, pp. 535-549; P.K. Weck and P.E. Cane, chap. 16, Comparative Biologic Activities of Human Interferons, Interferons and Their Applications, ed. P.E. Came and W.A. Carter, Springer Publisher, (Handbook of Experimental Pharmacology V. 71) 1984, Pp. 339-355.

Prior to the invention in U.S. Patent Application No. 448,951 dated December 13, 1982 (corresponds to DE 33 45 092 A1) - on their disclosure referred to here - it has no reports of that Ability of the interferon given the appetite and the To influence feed exploitation in warm-blooded vertebrates rivers. This application discloses that interferon is a has such effectiveness.  

There is a need for improved Processes to regulate appetite and effectiveness feed conversion in warm-blooded vertebrates. In the all known interferon research for finding their antivirus, antiproliferative or appetite legs The interferon doses used in the generally been high. The inventors now have over surprisingly found that much lower Dosages show superior effects.

The invention relates to the use of a biological active α-interferons in an oral dose of no more than 11 IU / kg (5 IU / lb) body weight per day for improvement the effectiveness of feed conversion and to increase the Weight gain in warm-blooded vertebrates. The currently preferred method is the administration of human chem α-interferon orally at a dose between approximately 0.22 and 3.3 IU / kg (0.10 and 1.5 IU / lb) body weight per day. A  Treatment on three consecutive days is preferred although other administration plans can also be created.

The present invention enables an effect on α-Inter Ferondosen, which are much smaller than those previously used are. In addition to the beneficial biological effects the use of lower dosages these procedures themselves understandably less expensive. Procedure according to the Invention in animal species such as cattle, pigs, Goats, sheep, poultry, cats, dogs and horses and can also be applied to humans.

The α-interferon administered can be more heterologous or homologous Origin. ("heterologous origin" means that the Interferon was obtained from cells of a genus that are different from that to which it is administered).

The optimal dosage of α-interferon fluctuates to some extent Extent from species to species and probably from animal to species Animal. Effects that are similar to those with a given daily dosage, administered for a  given number of days can be reached, he too be targeted by taking a slightly lower dosage for a slightly larger number of days or one slightly higher dosage for a slightly smaller one Number of days administered. Accordingly, the dose to be reduced somewhat to the to obtain the same biological effect if the animal has a Infection that it excretes from something natural Interferon causes.

The earlier patent application, US no. 448,951 of December 13th 1982 the applicant (DE 33 45 092 A1) discloses that the appetite of warm-blooded Vertebrates can be affected by a method that is characterized in that the warm-blooded vertebra animals a biologically active fraction interferon in one Amount administered to change feed intake of the animal or the effectiveness of feed conversion is sufficient. The application discloses that interferon can be obtained from any Can use cells, this also includes genetic engineering set interferon. Fibroblast interferon, which in Bovine breed cells are found to be suitable net interferon indicated; oral administration is one preferred form of treatment. The following description shows that such effects can be achieved by uses low doses of interferon.

The method of the invention can be carried out with α-interferon which can be obtained by customary methods. A particularly suitable method for producing an interferon is described below.  

example 1

Human alpha interferon can be by means of the following Process, which is generally called Cantell process is drawn, manufactured. The procedure goes out of bundles of human leukocytes, which in this case from the Gulf Coast Regional Blood Center, Houston, Texas, were obtained. The leuco contained in these containers cyten films are collected in centrifuge bottles and then diluted with 0.83% ammonium chloride. The mixture is incubated with interrupted shaking for 15 minutes and is then centrifuged at 2000 rpm for 20 minutes. The any excess liquid is discarded. The cell pellets in a minimal volume of sterile, phosphate-free buffered saline (PBS) resuspended. The mixture is then diluted with ammonium chloride and centri fugated. The supernatant liquid is discarded again. The remaining cell pellets are kept to a minimum Volume of tissue culture medium, e.g. B. a minimal essential medium (MEM) available from KC Biological, resuspended. The cell concentration is measured using a Coulter counter certainly.

Interferon induction takes place in glass or plastic bottles. The induction medium contains MEM, 75 mM Hepes (available from Calbiochem), 75 mM Tricine (available from Sigma Chemical Co.), human agamma serum (18 mg / ml) and gentamycin sulfate (from M.A. Bioproducts; 50 mcg / ml). The cells are in the Induction vessels up to a final concentration of approx Given 5 to 10 million cells per milliliter. The In the production vessel is incubated in a water bath at 37 ° C, and alpha interferon is added as a primer.  

After two hours, the induction mixture with Sendai virus transferred. This causes the production of alpha interferon in the supernatant fluid through the leukocytes. After the incubation time is 12 to 18 hours centrifuged mixture. The cells are discarded; the Any excess liquid is cleaned.

The raw interferon is heated to 10 ° C or less in an ice bath chilled. 5 molar potassium thiocyanate is added until one receives a final concentration of 0.5M. The solution turns 15 Minutes stirred; then their pH is adjusted to 3.3 Addition of hydrochloric acid reduced. The mixture turns on finally centrifuged at 2800 rpm for 30 minutes; the supernatant liquid is discarded.

The pellets are then resuspended in 95% ethanol and Stirred for 15 minutes. This suspension is at 20 minutes Centrifuged at 2800 rpm. The pellets are discarded. Of the pH of the supernatant liquid is then with Sodium hydroxide set to 5.8. The mixture turns 10 Stirred minutes and then 20 minutes at 2800 rpm centrifuged. The pellets are discarded. The pH of the Supernatant liquid is then mixed with sodium hydroxide set to 8. This solution will take 10 minutes stirred, followed by centrifugation at 2800 rpm for 20 minutes. The supernatant liquid is discarded. The pellets are mixed with 0.5M potassium thiocyanate in a 0.1M Sodium phosphate buffer resuspended. This suspension will stirred at 4 ° C.

The suspension is then at 2800 rpm for 20 minutes centrifuged for a long time. The pellets are discarded. The pH the supernatant liquid is adjusted to 5.3 with hydrochloric acid set. After stirring and centrifuging for 10 minutes  the pH of the supernatant liquid with hydrochloric acid set to 2.8, followed by another 20 minutes Stir. This mixture is centrifuged at 2800 rpm. The pellet obtained is purified human alpha interferon.

The pellet is made up with 0.5M potassium thiocyanate in 0.1M sodium phosphate buffer with a pH of 8.0 resuspended. It will then against PBS at 4 ° C with two exchanges of the PBS dialyzed. This mixture is then zen centrifuged; the precipitation is discarded. The received purified alpha interferon is obtained by filtration through a Sterilized 0.2 micron filter.

A human alpha interferon is made according to this procedure by Immuno Modulators Laboratories, Inc., Stafford, Texas, manufactured and sold under the trademark Agriferon ± -C ver drove.

There are other methods for the preparation known to the person skilled in the art Position of interferons available, e.g. B. from alpha-Inter feron and human gamma interferon. So describe e.g. B. U.S. Patent Nos. 4,376,821 and 4,460,685, methods of manufacture of human gamma interferon. A method of manufacture The position of bovine fibroblast interferon is in the above mentioned patent application of the applicant disclosed.

Example 2

This trial shows effective routes for administration and dosage of human alpha interferon as an auxiliary agent in the prevention and / or treatment of IBR virus infections in cattle. 36 calves aged 9 to 12 Months and weighing between 436 and 648 pounds  from the Texas Agricultural Experiment Station, Amarillo, Texas related. The calves were divided into three weight groups divided and arbitrarily transferred to treatment groups. Treatment with human alpha interferon was done oral (OS), intranasal (IN) or intravenous (IV). Table 1 shows the number of calves for each route of administration and the dosage.

Table 1

Number of calves treated with different routes and doses of interferon

Control calves received MEM as a placebo. The interferon was administered daily for three consecutive days starting from the time of inoculation with a virulent IBR virus (Cooper strain) obtained from the National Animal Disease Laboratory, Ames, Iowa. The exposure dose of this virus was 10 ^6.6 TCID₅₀ per calf. The calves were seronegative for IBR virus at the time of virus exposure.

IBR virus inoculations were performed intranasally using a Syringe given in a 2 ml dose per nostril. Body weight and rectal temperatures were recorded periodically. Blood samples were taken for serum interphone and serum anti each calf body measurements taken. Nasal swabs were made for the Virus isolation taken. Nasal tampons were used to get nasal secretion samples for interferon determination hold.

The results of the table are shown below. Table 2 shows the rectal temperatures of the calves different times after inoculation. Table 3 shows the IBR virus titer in the nasal secretions of the calves. Table 4 shows the interferon titer in the nasal secretions of the calves. Table 5 shows the serum antibody titers for IBR virus. Table 6 shows the calf's feed consumption (measured using target devices from UIS Inc., Cookeville, Tennessee). Table 7 shows performance data for the calves. Table 8 shows mortality and performance data.

Table 4

Geometric mean interferon titer in nasal secretions

Table 5

Geometric medium antibody for IBR virus after exposure

Table 7

Weight change after 14 days

Table 8

Mortality and weight change after 27 days

The calves showed a fever increase of more than 40 ° C on the third day after inoculation and returned return to normal temperature on day 14; this shows successful viral exposure. At the highest most interferon dosing in oral or intranasal Administration increased the fever by one day hesitates.  

Simultaneously with this rise in temperature, there was one Increase in geometric mean IBR virus titer speaking Table 3. If interferon intranasally at the highest dose was administered, a signifi edge increase in geometric mean titer on day 3 in Compared to the other intranasal dosages. If however, the interferon given orally was different the highest dose significantly on day 9 compared to the other oral dosages. This could be due to an over Dosage of the interferon indicate an increase virus excretion. The peak of IBR virus excretion occurred latest in the lowest oral group Dosages on. All three groups treated orally divorced more viruses than the control animals on day 9, but only the group with the highest oral dose was significant higher than that of the control animals. The maximum IBR Virusex cretion occurred on day 5 in the middle and low intranasal dosage, but in on the 2nd day the group of the highest intranasal dosage. In the Group of highest oral doses were made up of more viruses divorced. With both oral and intranasal Administration resulted in the lowest dose lower IBR virus excretion on the 2nd and 3rd day, this however, was higher during the later stages of the infection. Observations of the calves with intranasal dosing showed that swallowed most of the dosage used and some was expelled from the nasal passages so that the intranasal route appears to be an ineffective method.

On the 4th day after inoculation, IBR virus antibodies were raised discovered in all calves. IBR virus antibodies were not by any dosage or route of administration of the Interferons delayed.  

Calves that have human alpha interferon at the highest received oral dosage, consumed significantly less Food as% body weight compared on the 5th, 6th and 9th day to the other groups with oral dosing. The significant reduced feed intake at the highest oral dosage, the of no difference between the lowest oral Dosage and control animals was accompanied shows that high interferon doses for appetite control purposes solutions are less desirable than low doses.

While all the other groups lost weight, they lost weight Calves with the lowest oral dose during the Fortnightly period of viral infection gained weight. The The group with the highest oral dose showed one significantly less weight loss on day 14 than that Group with the lowest oral dosage or as that Control animals. Although four of the calves are more bacterial Pneumonia died, no pathology could be observed which was associated with interferon administration.

Overall, human alpha interferon appears orally ver at the lowest dose (39.6 IU / kg) the best form of administration and dosage. More Inter feron doesn't seem to be better than less.

Example 3

This trial shows the effective oral dosage of Inter feron to produce an antiviral effect virulent IBR virus in an exposure model. Fourty Weighing calves between the ages of 9 and 12 months from 195.2 to 340.5 kg were from the Texas Agricultural Experiment station related. The calves were divided into five groups  divided into eight calves each with the same weight. Each group underwent random treatments. The Treatment groups were approximately 0, 0.02, 0.22, or 2.2 22.0 units of human alpha interferon per kg Body weight administered. The 0 treatment group received MEM as a placebo.

Starting two days prior to exposure to the virulent IBR virus, the calves were given single daily oral doses of interferon (or placebo) for three days, with the final dose on the day of inoculation. IBR virus inoculations were carried out with a syringe in a 2 ml dose per nostril (10 ^6.6 TCID₅₀ per calf). All of the calves in this study were seronegative for IBR virus at the time of inoculation. Seven calves were removed from the study because two of them developed IBR virus antibodies on the day of inoculation and five did not eat food from the feed consumption meter.

Table 9 shows the number of calves with the opposite level interferon dosage; Table 11 shows a summary summarizing these results. The feed / gain ratio in Table 11 shows the amount of feed consumed in kg, divided by the increase in kg within the first eleven days again.  

Table 9

Interferon dosing

Table 10

Geometric mean IBR virus titer in nasal secretions (plaque-forming units)

Table 11

summary of results

Calves weighing approximately 2.2 units per kg of body weight (group D) showed the shortest duration of fever and the lowest fever peak of all groups. The highest in terferon dosing was significantly disadvantageous as it turned out results in higher fever and less weight loss. Of the Group D dosage antivirus protection, 0.43 to 0.59 A. units per kg is shown in Table 10. Three days after Group D calves were significantly different from virus inoculation fewer IBR viruses than the control animals (26,000 plaque forming units versus 193,000 PFU). Seven days after  Group D calves were still divorced from virus inoculation fewer viruses (29,000 PFU versus 86,000 PFU), though the difference was not significant. All calves divorced no viruses on the 14th day after inoculation.

Most calves in all groups lost after the IBR virus exposure weight, and then increased during the Duration of the examination to gain weight. The group D calves had the lowest weight loss during infection and the biggest weight gain at the end of the exam, as can be seen from Table 11. The interferon dosage has a significant negative correlation with weight loss of after interferon administration and the virus inoculation occurred in groups A to D.

This confirms the results of Example 2 and provides further clear that the most effective dose of human alpha interferon an exceptionally low oral dose is. The dosage of about 2.2 IU / kg body weight results reduced virus excretion, the shortest fever duration, the lowest weight loss, the lowest fie top, the largest average daily weight gain and the best feed conversion.

Example 4

This experiment shows the practicality and the economy benefits of administering human alpha inter feron on calves with a mixed viral infection tion in a transport fever model. The calves became like this kept as close as possible in an actual Experienced marketing system. Forty calves were from one Acquired buyers in Tennessee in a similar manner how this is done in a breeding calf farm, and were per  Trucks to Amarillo, Texas (1,899 km) within Transported 24 hours without feed or food. The calves were between 9 and 12 months old, weighed 183.9 to 247.4 kg and were from the buyer in various auction markets in the southeastern United States.

The calves were divided into three treatment groups, with Ear tags provided for identification and arbitrary Treatment groups assigned: ten calves received one oral dosage from 2.2 to 3.3 units / kg; ten calves received two oral doses at the same dose consecutive days and twenty calves served as untreated control animals. The last interferon dose was given two days before transportation.

When they arrived at the breeding station in Amarillo, the Calves weighed and their rectal temperatures measured. On finally the calves were fed food and water. At the the next day they were treated, weighed again and theirs Temperatures determined. The treatment consisted of deworming, Four-way clostridium bacterin, delousing with an external Insecticide, an injection of A and D vitamins and one Blood collection for serology.

There was a natural outbreak of transportation fever, and three calves died of pneumonia: a control animal and two animals given a dose of interferon was.

The ten calves had 37 days after treatment two interferon doses have been given prior to transportation were a significantly greater weight gain than the Kon troll calves. The calves with one dose took better too than the control animals, but not as well as the calves  with two doses. The calves with interferon walked food ingested better in gaining weight than the control animals around. The favorable results of the Be action are summarized in Table 12.

Table 12

Advantages of HuIFN-A in transport-stressed breeding calves

Example 5

Forty breeding calves were randomly treated in four groups of ten calves each. All calves were IBR virus seronegative. The calves received placebo or interferon (human alpha) orally at three under different doses (0.11, 1.1 or 11.0 IU / kg body Weight). A dose of interferon or placebo was given on Day before, day after and day of IBR virus inoculation given. Each calf received 103 plaque forming units (PFU) IBR virus per nostril.

Tables 13 to 18 show the results of this test.

Table 13

Number of calves with a temperature of at least 40 ° C

Table 14

Average daily increase 14 days after inoculation

Table 15

Feed consumption and increase for 14 days after inoculation

Table 16

Feed consumption and increase for 27 days after inoculation

Table 17

Geometric mean serum antibody titers against IBR virus

Table 18

Geometric mean IBR virus titer (plaque-forming units) in the nasal secretion

The rectal temperatures of the cattle did not differ significantly among the four treatment groups after one Inoculation with the IRB virus. As Table 13 shows however, more calves dosed at 1.1 IU / kg fever with at least 40 ° C in the five to nine days after Inoculation period.

Tables 14 and 15 show that the calves with 1.1 IU / kg Dosages increased significantly within the first 14 days Weight gain than the control animals and improved Had feed conversion. The results for weight gain and feed / weight gain ratio at 27 days all three of the treated groups compared to the comparison animals, but not in a significant way, as it turns out Table 16 shows.

IBR virus antibodies were raised by all groups. Table 17 shows that the formation in significantly faster of the group treated with 1.1 IU / kg. The nasal Excretion of the IBR virus also occurred at the 1.1 IU / kg treatment  group, as shown in Table 18. Significantly more viruses were identified from the 1.1 IU / kg group divorced, at three days compared to the Control animals (221 PFU versus 2 PFU) and also after seven Days (20,749 PFU versus 204 PFU) after the virus inocula tion. After 14 days, the control animals excreted more Viruses than any other interferon-treated Group from (12,078 PFU versus 298 or 7 or 132 PFU). These data show that the initial viral infection at Interferon-treated calves intensified and shortened has been resulting in faster recovery and better Achievements.

In summary, stimulates human alpha inter feron when administered orally in an amount of 1.1 IU / kg Body weight significantly the development of antibodies, improves weight gain at 14 days after IBR virus inoculation and increases IBR virus excretion 3 and 7 days, but reduced virus excretion at 14 Days after inoculation. This dosage improves the Effectiveness of feed utilization during the first 14 days.

Claims (4)

1. Use of a biologically active α-interferon in a oral dosage of no more than 11 IU / kg body weight per day to improve the effectiveness of feed consumption tion and to increase weight gain in warm-blooded animals vertebrates. 2. Use according to claim 1, characterized in that the α-interferon is human α-interferon. 3. Use according to claim 1 or 2, characterized in that that a dosage between 0.22 and 3.3 IU / kg body weight per lay used. 4. Use according to claim 3, characterized by a oral interferon dosage between 0.22 and 3.3 IU / kg Body weight per day for three consecutive days.