Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-13
2002-10-15
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S241000, C514S275000
Reexamination Certificate
active
06465460
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the treatment and prevention of diseases caused by protozoan parasites in man and in animals. In particular, the invention relates to novel compositions and methods for parenteral treatment and prevention of protozoal diseases, e.g., Piroplasmosis, Babesosis, Toxoplasmosis Neospora caninum, Crytosporidiosis and Equine Protozoal Myeloencephalitis.
BACKGROUND OF THE INVENTION
Protozoan parasites (also known as apicomplexan parasites) cause a variety of clinical disease manifestations in both man and animals. For example, hemoprotozoan parasites of the Babesia genus, namely
Babesia caballi
and
Babesia equi
, are responsible for the economically devastating disease, equine piroplasmosis. Equine piroplasmosis is widely distributed worldwide although it is most prevalent in the tropics, sub-tropics and temperate regions (see, Robinson, Edward N., “Current Therapy In Equine Medicine”, Vol.2, pp.299-300, (1987) (ISBN: 0-7216-14914)).
The principal mode of transmission of the protozoan is via a tick vector, e.g.,
Dermacentor nitens
. Clinical manifestation of acute infection is characterized by depression, fever, anorexia, icteric mucous membranes, ecchymotic hemorrhages and edema of the extremities and ventral abdomen. Death can occur within 24-48 hours and mortality rates in outbreaks may be high (see, Robinson, Edward, N., “Current Therapy in Equine Medicine”, Vol. 3, pp. 499-500 (1992) (ISBN: 0-7216-3475-3)).
Horses which test positive for piroplasmosis (complement fixation or indirect flourescent antibody tests) are rarely allowed to enter the United States without first undergoing treatment for the disease or under rigid guidelines (see, Brooks, L., “Piroplasmosis: The Olympic Question”, The Horse, pp. 43-48 (July 1996)). Currently recommended treatment regimens include the use of imidocarb dipropionate (Burroughs Welcome Co.) and often the treatment produces adverse side effects which include salivation, restlessness, colic and gastrointestinal tract hypermotility (see, Kobluk, Calvin N. et al., “The Horse Diseases & Clinical Management”, Vol. 2, pp. 1084-1885 (1995) (ISBN: Vol.2 0-7216-5984-5)). Moreover, treatment with imidocarb dipropionate has met with marginal success, especially when the etiologic agent is
Babesia equi
(50% to 60%) (see, Reed, Stephen M. et al., “Equine Internal Medicine”, pp. 570-571 (1998) (ISBN: 0-
7216-3524
-5)).
Thus, there is a need in the art for an effective anti-protozoal agent and a method of treatment and prevention of Piroplasmosis which does not produce the adverse side effects seen with current treatment regimens.
Other examples of blood borne protozoal infection caused by Babesia spp. include: babesiosis of cattle, e.g.,
Babesia bigemina
and
Babesia bovis
; caprine and ovine babesiosis, e.g.,
Babesia ovis
; and canine babesiosis, e.g.,
Babesia canis
and
Babesia gibsoni
(see, Smith, Bradford P., “Large Animal Internal Medicine” pp.1088-1092 (1990) (ISBN: 0-8016-5062-3)). See also, Bonagura, John D. “Kirk's Current Veterinary Therapy XII Small Animal Practice”, Vol. 12, pp. 315-319, (1995) (ISBN: 0-7216-5188-7)). Likewise, there is a need in the art for a safe, effective and economical treatment for such infections.
In humans, for example, protozoan infections can cause severe disease manifestations. A common sequella in patients suffering from acquired immune defficiency syndrone (AIDS) is
Cryptosporidium parvum
infection (Cryptosporidiosis) which produces severe chronic and often fatal diarrhea. The parasite is found worldwide and lives in cattle and domestic animals and is excreted in feces. It can be transmitted to humans directly from animals or through contact with feces, contaminated water or food (see, e.g. “National Institute of Allergy and Infectious Diseases—AIDS-Related Cryptosporidiosis”, www press release (March, 1991)).
Many attempts have been made to find a threapeutically effective treatment for this disease. One family of drugs currently used in the veterinary profession for the treatment of coccidosis, the triazine-based anticoccidial agents (e.g., triazinediones and triazinetriones) especially diclazuril and letrazuril, have been tried experimentally in the treatment of crytosporidiosis in man (see, National Library of Medicine, AIDSDRUGS Database, DRG-0079 (Jan. 22, 1998); and (National Library of Medicine, AIDSTRIALS Database, FDA-038B (Apr. 25, 1990)). These compounds are formulated for oral administration and have met with limited success due to poor absorption. The best response to such drugs has been seen in persons with the highest blood levels post adminsitration (see, AIDS Treatment News, No. 111 (Sep. 21, 1991)).
To date, however, there is still no efficacious therapy for Cryptosporidial infections in man (see, Health Canada, Laboratory Centre For Disease Control: Material Safety Data Sheet—48
, Cryptosporidium parvum
, Oct. 11, 1997 @ (www.hc-sc.gc.calhpb/lcdc/biosafty/msds/msds/48e.html (Jul. 24, 1999)). Accordingly, there still exists an urgent need in the art for a safe and effective pareneral formulation for the treatment and prevention of potozoal infections such as cryptosporidiosis or babesiosis.
Equine protozoal myeloencephalitis (EPM), a central nervous system disease which affects equine species, is also primarily caused by a protozoan parasite,
Sarcocystis neuroma
also known as
Sarcocystis falcatula
. The horse is not a normal host for this protozoan (the horse is not part of the normal life cycle) and is considered to be a dead end host. The definitive host is thought to be the opossum. Equids are infected with the S. neuroma organisms via ingestion of food or water contaminated with feces of an infected carnivore such as the opossum (see, Robinson, Edward N., Current Therapy in Equine Medicine: Fenger, Clara A., “Equine Protozoal Myeloencephalitis”, Vol. 4, pp. 329-333 (1997) (ISBN: 0-7216-2633-5)).
Recently, other protozoan parasites have been implicated as also playing an etiologic role in the pathogenesis of EPM, e.g., Neospora caninum and Toxoplasma species. Accordingly, there still exists a need in the art for an effective treatment of EPM which demonstrates broad spectrum efficacy against all protozoan parasites in the horse inclusive of the aforementioned organisms.
The clinical signs of EPM can vary from case to case. Generally, horses present neurological signs which are asymmetrical, and actual symptoms will vary depending upon the severity and location of lesions produced by the parasites in the brain, brain stem or spinal cord. Ataxia, incoordination and general weakness are usually present and can be accompanied by muscle atrophy (usually most notable in the rear limbs). There can be paralysis of the muscles of the eyes and face, drooping ears, difficulty swallowing (dysphagia) head tilt, altered gait, or even seizures and collapse. Recent reports of numbers of EPM cases indicate that the disease is far more widespread and serious than originally thought.
There is currently no vaccine available for prevention of this disease. Previously preferred treatment was aimed at control of the parasitic infection via the use of sulphonamides and pyrimethamine (see, U.S. Pat. No.: 5,747,476). However, these measures have been met with limited success. More recently, and due to the urgent need for a safe and effective treatment for this devastating disease, new methods of therapy and new agents have been explored, e.g., through the emergency FDA importation of anticoccidial agents such as diclazuril and toltrazuril (see, FDACVM publication: “Instructions for Personal Use Importation of Diclazuril” (Dec. 16, 1997); and FDACVM publication: “The Importation of Toltrazuril for Personal Use” (1997) which are available from the American Association of Equine Practitioners, Lexington, Ky. (AAEP)). (See also, U.S. Pat. No.:5,883,095).
It should be noted that the current emergency importation and treatment of horses with diclazuril and toltrazuril is speculative. Oral formulations adapted for use in the horse of one or mo
Hundley Bruce
Maclin Robert
Jagoe Donna
Krass Frederick
New Ace Research Company
Sutherland & Asbill & Brennan LLP
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