Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Derived from – or present in – food product
Reexamination Certificate
1997-03-05
2003-12-02
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Derived from, or present in, food product
C424S164100, C424S167100, C424S804000
Reexamination Certificate
active
06656468
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to Clostridial antitoxin therapy for humans and animals.
BACKGROUND OF THE INVENTION
Several species of Clostridia bacteria produce toxins of significance to human and animal health [C. L. Hatheway, Clin. Microbiol. Rev., 3:66-98 (1990)]. The effects of these toxins range from diarrheal diseases that can cause destruction of the colon, to paralytic effects that can cause death. Particularly at risk for developing Clostridial diseases are neonates and humans and animals in poor health (e.g., those suffering from diseases associated with old age or immunodeficiency diseases).
The bacterium
Clostridium botulinum
produces the most poisonous biological toxin known. The lethal human dose is a mere 10
−9
mg/kg bodyweight for toxin in the bloodstream. Botulinal toxin blocks nerve transmission to the muscles, resulting in flaccid paralysis. When the toxin reaches airway and respiratory muscles, it results in respiratory failure that can cause death. [S. Arnon, J. Infectious Diseases, 154:201-206 (1986).]
C. botulinum
is a spore-forming anaerobe whose habitat is soil and the mud of lakes and ponds. The spores are carried by dust and are found on vegetables taken from the soil, on fresh fruits, and on agricultural products such as honey. Under conditions favorable to the organism, the spores germinate to vegetative cells which produce toxin. [S. Arnon, Ann Rev. Med., 31:541 (1980).]
Botulism disease may be grouped into three types, based on the method of introduction of toxin into the bloodstream. Food-borne botulism results from ingesting improperly preserved and inadequately heated food that contains botulinal toxin. There were 355 cases of food-borne botulism in the United States between 1976 and 1984. [K. L. MacDonald et al., Am. J. Epidemiology, 124:794 (1986).] The death rate due to botulinal toxin is 12% and can be higher in particular risk groups. [C. O. Tacket et al., Am. J. Med., 76:794 (1984).] Wound-induced botulism results from
C. botulinum
penetrating traumatized tissue and producing toxin that is absorbed into the bloodstream. Since 1950, thirty cases of wound botulism have been reported. [M. N. Swartz, Microbiology, 4th ed. (1990).] Infectious infant botulism results from
C. botulinum
colonization of the infant intestine with production of toxin and its absorption into the bloodstream. It is likely that the bacterium gains entry when spores are ingested and subsequently germinate. [S. Arnon, J. Infectious Diseases, 154:201-206 (1986).] There have been 500 cases reported since it was first recognized in 1976. [M. N. Swartz, supra.] Infant botulism strikes infants who are three weeks to eleven months old (greater than 90% of the cases are infants less than six months). [S. Arnon, J. Infectious Diseases, 154:201-206 (1986).] It is believed that infants are susceptible, due, in large part, to the absence of the full adult complement of intestinal microflora. The benign microflora present in the adult intestine provide an acidic environment that is not favorable to colonization by
C. botulinum
. Infants begin life with a sterile intestine which is gradually colonized by microflora. Because of the limited microflora present in early infancy, the intestine is not as acidic, allowing for
C. botulinum
spore germination, growth, and toxin production. In this regard, some adults who have undergone antibiotic therapy which alters intestinal microflora become more susceptible to botulism.
An additional factor accounting for infant susceptibility to infectious botulism is the immaturity of the infant immune system. The mature immune system is sensitized to bacterial antigens and produces protective antibodies. Secretory IgA produced in the adult intestine has the ability to agglutinate vegetative cells of
C. botulinum
. [S. Arnon, J. Infectious Diseases, 154:201-206 (1986).] Secretory IgA may also act by preventing intestinal bacteria and their products from crossing the cells of the intestine. [S. Arnon, Epidemiologic Reviews, 3:45-66 (1981).] The infant immune system is not primed to do this.
Clinical symptoms of infant botulism range from mild paralysis, to moderate and severe paralysis requiring hospitalization, to fulminant paralysis, leading to sudden death. [S. Arnon et al., Epidemiologic Reviews, 3:45-66 (1981).]
The chief therapy for severe infant botulism is ventilatory assistance using a mechanical respirator and concurrent elimination of toxin and bacteria using cathartics, enemas, and gastric lavage. There were 68 hospitalizations in California for infant botulism in a single year with a total cost of over $4 million for treatment. [T. L. Frankovich & S. Arnon, West. J. Med., 154:103 (1991).]
Different types of Clostridium each produce antigenically distinct toxin designated by the letters A-G. Nearly all cases of infant botulism have been caused by bacteria producing either type A or type B toxin. (Exceptionally, one New Mexico case was caused by Clostridium producing type F toxin and another by Clostridium producing a type B-type F hybrid.) [S. Arnon, Epidemiologic Reviews, 3:45-66 (1981) Type C toxin affects waterfowl, type D toxin affects cattle, and type E toxin affects both humans and birds.
A trivalent antitoxin derived from horse plasma is commercially available from Connaught Industries Ltd. as a therapy for toxin types A, B, and E. However the antitoxin has several disadvantages. First, extremely large dosages must be injected intravenously and/or intramuscularly. Second, the antitoxin has serious side effects such as acute anaphylaxis which can lead to death, and serum sickness. Finally, the efficacy of the antitoxin is uncertain and the treatment is costly. [T. O. Tacket et al., Am. J. Med., 76:794-98 (1984) .]
A heptavalent equine botulinal antitoxin which uses only the F(ab′)2 portion of the antibody molecule has been tested by the United States Military. [M. Balady, USAMRDC Newsletter, p. 6 (1991).] This was raised against impure toxoids in those large animals and is not a high titer preparation.
A pentavalent human antitoxin has been collected from immunized human subjects for use as a treatment for infant botulism. The supply of this antitoxin is limited and cannot be expected to meet the needs of all individuals stricken with botulism disease. In addition, collection of human sera must involve screening out HIV and other potentially serious human pathogens. [P. J. Schwarz & S. S. Arnon, Western J. Med., 156:197-98 (1992).] Infant botulism has been implicated as the cause of mortality in some cases of Sudden Infant Death Syndrome (SIDS, also known as crib death). SIDS is officially recognized as infant death that is sudden and unexpected and that remained unexplained despite complete post-mortem examination. The link of SIDS to infant botulism came when fecal or blood specimens taken at autopsy from SIDS infants were found to contain
C. botulinum
organisms and/or toxin in 3-4% of cases analyzed. [D. R. Peterson et al., Reviews of Infect. Dis., 1:630-34 (1979).] In contrast, only 1 of 160 healthy infants (0.6%) had
C. botulinum
organisms in the feces and no botulinal toxin. [S. Arnon et al., The Lancet, pp. 1273-77, Jun. 17, 1978.)
In developed countries, SIDS is the number one cause of death in children between one month and one year old. [S. Arnon et al., The Lancet, pp. 1273-77, Jun. 17, 1978.] More children die from SIDS in the first year than from any other single cause of death in the first fourteen years of life. In the United States, there are 8,000-10,000 SIDS victims annually. Id.
What is needed is an effective therapy against infant botulism that is free of dangerous side effects, is available in large supply at a reasonable price, and can be safely and gently delivered so that prophylactic application to infants is feasible.
SUMMARY OF THE INVENTION
The present invention contemp
Carroll Sean B.
Clemens Christopher M.
van Boldrik Margaret B.
Medlen & Carroll LLP
Promega Corporation
Saunders David
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