Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-06-23
2003-06-10
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S322000
Reexamination Certificate
active
06576624
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to the use of dopamine receptor antagonists in palliative tumor therapy, particularly as agents for antagonizing side effects such as are frequently observed in tumor therapy by means of alkylphosphocholines, particularly miltefosine.
2. Background Information
It is known and described that the alkylphosphocholine miltefosine causes side effects in patients during the treatment of cancer. These also manifest themselves in patients treated with miltefosine by a marked loss of body weight (
Eur. J. Cancer
, Vol. 29 A, No. 2, pp. 208-209, 1993). Further side effects of the chemotherapy are: damage to the tissue with a high proliferation rate, leuko- and thrombopenia, decrease in erythrocytes, gastrointestinal disorders, loss of appetite, upper abdominal complaints, disturbed absorption and diarrhea, as well as loss of hair and also liver damage and hyperuricaemia.
In a dose-finding study by J. Verweij et al. (
J. Cancer Res. Clin. Oncol
118:606-608 (1992)), it was observed that most antiemetics (including 5HT
3
antagonists) were inactive in the prevention of vomiting and nausea. The smallest emetic effect was achieved if miltefosine was taken immediately after eating, domperidone being given 0.5 hours before eating in a dose of 20 mg. In the phase II studies of the same author which were carried out later (
Eur. J. Cancer
Vol. 29 A, No. 5 p. 779(1993), it was meanwhile found that it was not possible to prevent vomiting either by standard antiemetics or by 5HT
3
antagonists.
Since the loss of weight under tumor treatment with alkylphosphocholines leads to a further weakening of the already overloaded body, it was the object of the invention to characterize substances which, in combination with miltefosine or its derivatives, antagonize the known side effects of the alkylphosphocholines such as decrease in body weight.
It must be ensured here that the anti-tumor action of miltefosine or its derivatives is not abolished or reduced by combination with the antidote and no additional side effects occur due to the administration of the combination.
SUMMARY OF THE INVENTION
The above object has now been achieved in that agents for antagonizing side effects such as are frequently observed during tumor therapy by means of alkylphosphocholines, in particular miltefosine, have been found and prepared. These are dopamine receptor antagonists, particularly the two dopamine antagonists domperidone and pimozide. It is to be understood that these agents can be administered both in a fixed combination with the alkylphosphocholine and, in each case, in individual packs and sequentially.
REFERENCES:
patent: 4707484 (1987-11-01), Berger et al.
patent: 4883822 (1989-11-01), Matsuo et al.
patent: 0 273 168 (1988-07-01), None
“A dose-finding study of miltefosine (hexadecylphosphocholine) in patients with metastatic solid tumors”; Verweij, J. Planting, A., van der Burg M., Stoter, G.; Department of Medical Oncology, Rotterdam Cancer Institute/Daniel den Hoed Kliniek, The Netherlands; J Cancer Res Clin Oncol 1992; 118(8):606-8.
“Phase II study of daily oral miltefosine (hexadecylphosphocholine) in advanced colorectal cancer”; Planting AS, Stoter, G., Verweij, J.; Department of Medical Oncology, Rotterdam Cancer Institute/Dr. Daniel den Hoed Kliniek, The Netherlands; Eur J Cancer 1993; 29A(4):518-9.
Rote Liste 1998; Arzneimittelverzeichnis des Bundesverbandes der Pharmazeutischen Industre e. V. (BPI), des Verbandes Forschender Arzeimittelhersteller e. V. (VFA), des Bundesfachverbandes der Arzneimittel-Hersteller e. V. (BAH) und des Vergnades aktiver Pharmaunternehmen e.V. (VAP); ECV, Editio Cantor, Aulendorf/Wurtt.
“Effects of domperidone in patients with chronic unexplained upper gastrointestinal symptoms: a double-blind, placebo-controlled study”; Davis RH. Clench MH, Mathias JR; Department of Medicine, College of Medicine, University of Florida, Gainesville, Dig Dis Sci 1988 Dec; 33(12): 1505-11.
Nickel et al.: “D-21266: A New Antitumor Alkylphosphocholine Derivative with Less Side Effects”, Proc. Annu. Meet. Am. Assoc. Cancer Res., Bd. 38, 1997, p. A4102.
Verweij et al., “Phase II Study of Oral Miltefosine in Patients with Squamous Cell Head and Neck Cancer”, Eur J. Cancer, vol. 29A., No. 5, 1993, pp. 778-779.
Willis et al., Pharmacol., Biochem. Behav., 31(1), 69-73.
Frussa-Filho et al., Braz. J. Med. Biol. Res., 24(6), 611-14.
Spruse et al., J. Cancer Res. Clin. Oncol., 119(3), 142-9.
Engel Jürgen
Hilgard Peter
Klenner Thomas
Nickel Bernd
Goldberg Jerome D.
Pillsbury & Winthrop LLP
Zentaris AG
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