Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-23
2002-08-06
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06429211
ABSTRACT:
FIELD OF THE INVENTION
Field of the Invention: The present invention relates to a praziquantel composition for treating animals infected with parasites that cause abortigenic or neurologic diseases. More specifically, the present invention relates a praziquantel composition that is useful in treating parasitic protozoa such as coccidia that cause abortigenic or neurologic diseases of mammals.
Brief Description of the Prior Art: In protecting and treating various mammals, insects and fish from diseases caused by protozoa suspected of causing neurologic and/or abortigenic diseases, the art has used a number of compounds, recent among which are triazineone compounds. Generally, protozoa that are sensitive to these compounds include parasites that infect the intestines of birds, mammals and insects causing diarrhea, wasting disease, nausea and vomiting. Recently it has been found that some parasites that pass through the blood brain barrier, as well as parasites that pass through the placental barrier can be treated with the triazineones. Illustrative of parasites that are now known to cross the blood brain barrier or the placental barrier are those causing coccidial diseases such as
Toxoplasma gondii, Sarcocystis neurona, Neospora caninum, Neospora hugesii,
and
Isospora suis.
Illustrative of the triazineone compounds are triazinediones such as diclazuril compounds, and triazinetriones such as toltrazuril compounds. See U.S. Pat Nos. 4,933,341; 4,935,423; 5,114,938; 5,141,938; 5,188,832; 5,196,562; 5,256,631 and 5,464,837.
While other art-related compounds pertinent among which is praziquantel (2-acyl-4-oxo-hexahydro-4H-pyrazino[2,1-a[isoquinoline derivatives) are disclosed for use in treating parasites, the disclosure lacks any teaching or suggestion relating to the compounds as being useful in treating parasites that cross the blood or placental barrier. Generally, praziquantel has been used by itself or in combination with other compounds to formulate anthelmintic compositions for treating infestation of cestodes and nematodes and the like. See U.S. Pat. No. 4,001,411, 4,447,414, and 5,824,653.
U.S. Pat. No. 5,663,155 discloses praziquantel for use in the prevention and treatment of parasitic infections, which cause diseases such as malaria, trypanosomiasis, leishmania, schistosomiasis and elephantitis. The patent also suggests that praziquantel could be used to treat parasitic infections limited to the blood, lymph and tissues. Toxoplasmosis and Sarcocystis are specifically mentioned in the context of their infection of muscle tissues or intestines. There is no mention of treatment or prevention of diseases wherein the Toxoplasma, Sarcocystis, Neospora or Isospora is embedded into the brain of adult mammals or passed through the placental barrier to infect central nervous tissues of the fetus, producing abortion or weak newborns.
Generally, the mode of action of the triazineones is to attack the intermediate parasite stages found in the gut and intestinal wall cells, causing the endoplasmic reticulum, the perinuclear space and the mitochondria of the parasite to swell. This purportedly disturbs the ability for nuclear divisions causing the schizonts and microgamonts to remain small, forming only a few merozoites and microgametes respectively. The end result is reported to be the loss of the ability of these latter stages of the parasites to penetrate new mammalian cells, effectively halting the replication of the parasite in the host.
The mode of action of paraziquantel, as disclosed by U.S. Pat. No. 5,663,155 (ibid.), is related to the disruption of enzymatic processes of the parasite that relate to the metabolism of purine derivatives and purine-like chemical structures. Parasites are acutely sensitive to interference of these processes, thus compositions that specifically target these processes can be used to selectively eliminate a parasitic infection. Praziquantel is administered so as to attack parasites that are related to muscle tissue, intestine or blood infection. There is no mention of treating parasites of the central nervous system (brain and spinal cord) or parasites that can pass the placental barrier.
While the art has been concerned with protozoa suspected of causing neurologic and/or abortigenic diseases of mammals since the 1970s, successful isolation and in vitro cultivation of some of these protozoa proved to be difficult. For example, successful isolation of parasites from the brain or cerebral spinal fluid was not accomplished until the late 1980s. However, once it was determined that neurologic diseases could be produced by protozoa infecting the brain, and abortigenic diseases could be produced by protozoa infecting the fetus, there was a need for effective anti-protozoa drugs which could cross the blood-brain barrier and the placental barrier without producing deleterious side effects. Very few drugs are able to pass the blood-brain barrier or the placental barrier of mammals. Unfortunately, many of the art-known drugs that do cross the blood-brain barrier and/or the placental barrier to effectively treat parasitic infections of the brain have detrimental side effects such that they cannot be used without great risk. Therefore, there have been no effective drugs approved to date which provide an effective treatment for such neurologic or abortigenic diseases.
It is noteworthy that based on the disclosed mode of action of praziquantel in U.S. Pat. No. 5,663,155, relative to its broad attack on enzymes which affect purine metabolism, one would have expected that this compound might also produce deleterious effects if used to treat mammals with parasitic brain infections.
The following is a brief description of the parasitic diseases of the immediate invention, which are treatable with praziquantel. Equine Protozoal Myeloencephalitis (EPM) is a neurologic disease of horses, with a predilection for young horses undergoing stress (e.g. thoroughbred racehorses and purebred performance horses), and is thus a disease with significant monetary impact for the horse industry. EPM, first recognized as a disease in the 1970s, was not cultured from a horse with EPM and given the name
Sarcocystis neurona
until 1991. In 1997, a Neospora spp., now named
Neospora hugesi,
was isolated from the brain of a horse with EPM. Accordingly, it is now proposed that EPM may be caused by this newly recognized organism alone, by
Sarcocystis neurona
alone or the combination of the two.
Another coccidial parasite,
Toxoplasma gondii,
has been known for some time and was first isolated from the intestines and muscle tissue of cats. The definitive host for this parasite is the cat that can harbor the organism for long periods of time spreading oocysts to other animals including bovines, ovines, porcines and humans. Infection of sheep, cattle and humans has been associated with abortion and congenitally acquired disorders, which primarily affect the central nervous system. It has also recently been associated with abortion and malformation in kittens born to infected queens that had been seronegative prior to infection during pregnancy. Non-feline hosts such as bovines, ovines, porcines and humans do not produce oocysts but develop and may suffer from invasion of muscle and brain by tachyzoites and bradyzoites which produce the clinical signs of disease—neurological symptoms and abortion with fetal defects. It has been reported that 60% of cats are serologically positive to
T. gondii.
Once again, there is no approved treatment or prophylactic for toxoplasmosis.
Yet another coccidial parasite,
Neospora caninum
which was first isolated from dogs in 1988, produces both a neurologic and abortigenic disease in animals. It was previously confused with
Toxoplasma gondii.
The disease caused by this parasite occurs most severely in transplacentally infected puppies and is characterized by progressive ascending paralysis in the puppies, particularly of the hind limbs; polymyositis and hepatitis may also occur. This disease has more recently been recognized as a major c
Akorli Godfried R.
Bayer Corporation
Gil Joseph C.
Weddington Kevin E.
LandOfFree
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