ANTI-MALARIAL COMPOSITION AND METHOD OF USE

Abstract: Anti-malarial compositions for prophylactic or therapeutic treatment of vertebrates exposed to malaria parasites are disclosed. These compositions comprise one or more pyrimidine analogue inhibitors of nucleic acid biosynthesis, e.g., 5-fluoro-orotic acid, alone or together with one or more ''rescue'' compounds, e.g., a normal pyrimidine base or nucleoside that can be used by the host vertebrate, but not by malaria-causing parasites, for nucleic acid biosynthesis. Also claimed are methods of prophylactic and therapeutic use of these compositions.

Description: ANTI-MALARIAL COMPOSITION AND METHOD OF USE BACKGROUND OF THE INVENTION Field of the Invention This invention relates to compositions useful in the treatment of humans and other vertebrates infected with malaria parasites. More particularly, this invention relates to prophylactic and therapeutic compositions containing as active ingredients one or more substances that are toxic to the malaria-causing parasite alone or in combination with one or more substances that rescue the host vertebrate from the toxic effects of the anti-parasitic compositions. This invention also relates to the use of the aforementioned compositions for the prophylactic and therapeutic treatment of malaria in animal and human patients. Description of Related Art Malaria is a debilitating and often fatal disease caused by protozoans of the genus Plasmodium. According to World Health Organization estimates about 2.2 billion people live in areas in which malaria is still endemic, but control measures have decreased the level of toxicity; however, over 350 million people live in areas of the world in which malaria is highly endemic and no special antimalarial measures are being applied. "Science at Work: Special Programme for Research and Training in Tropical Diseases", UNDP/World Bank/WHO, Geneva, 2d ed., 1986. Currently, quinine-based drugs, particularly chloroquine, are the mainstay of anti-malarial chemoprophylaxis, particularly for those species for Plasmodium that are sensitive to this drug, i.e., P.knowlesi. P.vivax, P.ovale. P.malariae. P.yoelii and cloroquine-sensitive P.falciparum [Herwaldt, B.L. , et al. f Antimicrob. Agents Chemotherap.. 32:953 (1988); Krogstad, D.J., et a . , Id. , p. 957]. There are several important problems attendant upon the use of chloroquine as an anti-malarial. Although oral chloroquine typically is well-tolerated, some patients experience serious side effects. In addition, the safety of parenteral chloroquine has been questioned because it may cause cardiac arrhythmia and sudden death in children. Krogstad, et al. 1988 at 957. Further, P.falciparum strains resistant to chloroquine and other traditional drugs are known in at least 40 tropical and subtropical countries [Payne, D. , Parisitol. Today. 3:241-5 (1987); Wyler, D.J., N. Enσ. J. Med.. 308, 875 (1983)]. In areas with chloroquine- resistant P.falciparum. combination therapies have been recommended (chloroquine plus pyrimethamine-plus- sulfodoxine) , but the latter components are known to cause severe, even fatal, reactions [Herwaldt et al. 1988, at 953]. Furthermore, correlations between the in vitro suspectibility of parasites to chloroquine, mefloquine or other anti-malarial agents and clinical effectiveness are known to be very imprecise, and are more qualitative than quantitative [Herwaldt et al. 1988, at 953]. The future of malarial chemotherapy is particularly alarming in view of parasite strains that display cross-resistance to several structurally unrelated drugs [Hubbert, T.E., et al. , 35th Ann. Mtg. Amer. Soc. Trop. Med. Hyg., Denver, CO, 1986; Webster, H.K. , et ______ . , Am. J. Trop. Med. Hvσ.. 34:228-35 (1985)]. Thus, it is important to develop novel anti alarial drugs, particularly those that are effective against strains of malaria-causing parasites that display single or multiple drug resistance. The erythrocytic phase of the life cycle of P.falciparum is associated with clinical symptoms of malaria. During this 48 hour asexual cycle, each parasite inside a red blood cell generates 6 to 24 offspring that burst out and individually invade fresh erythrocytes. The exponential increase in parasites requires a steady supply of purine and pyrimidine nucleotides for the DNA and RNA synthesis necessary for their growth. Malarial parasites are able to use the rich pool of adenine nucleotides inside the erythrocytes to obtain their supply of purines, but these parasites, lacking the "salvage" pathway, cannot use preformed pyrimidines and, thus, must synthesize them de novo [Sherman, I.W., et al. , Microbiol. Rev. , 43:453-96 (1979); Reyes, P., et al. , Mol. Biochem. Parasitol.. 5:275-90 (1982); Rathod, P.K. , et al. , J ^ Biol. Che . r 258:2852-5 (1983)]. In contrast, mammalian cells are able to utilize preformed pyrimidine bases and nucleosides by salvage pathways [Jones, M.E., Ann. Rev. Biochem. , 49:253-79; Moyer, J.D., et al. , J. Biol. Chem.. 260:2812-18 (1985)]. These distinctions in pyrimidine metabolisms between malaria parasites and the cells of host mammals have led to the present discovery of anti-malarial prophylactic and therapeutic compositions that are lethal to such parasites, but not toxic to the host vertebrates harboring these parasites. Butrnnwry nψ -the Invention This invention provides compositions that inhibit the growth of malarial parasites in parasite-infected vertebrates, but which are without deleterious effects on the host vertebrate. It has now been discovered that certain pyrimidine analogues that inhibit de novo pyrimidine metabolism and are toxic to vertebrate cells can be used to inhibit the growth of malarial parasites and in parasite-infected vertebrates in vivo. It has also been discovered that the toxic effects of the aforementioned pyrimidine analogues on the cells of malaria parasite-infected vertebrates can be alleviated, if necessary, by the administration to intact vertebrates in vivo, of "rescue" compounds, e.g., normal pyrimidine bases or nucleosides that support the "salvage" pathway of pyrimidine metabolism. Thus the vertebrate can be "rescued" from both the effects of the parasites and the potentially toxic effects of the pyrimidine analogues used to prevent parasite proliferation. It is, therefore, an object of this invention to provide prophylactic and therapeutic compositions for vertebrates exposed to malaria parasites and malaria parasite-infected vertebrates. These compositions comprise one or more pyrimidine analogues that block de novo pyrimidine, and thus nucleic acid, biosynthesis, alone or together with a "rescue" compound, e.g., one or more normal pyrimidine bases or nucleosides that by-pass the effects of the blocked de novo pyrimidine biosynthesis pathway in the host vertebrate, but not in the parasites. A further object of this invention is to provide pyrimidine analogue compositions that are toxic to malaria parasites jLn vivo. Yet another object of this invention is to provide pyrimidine bases and nucleosides that are capable of rescuing the malaria parasite-infected vertebrate, but not the parasites themselves, from the toxic effects of the pyrimidine analogues. It is still another object of the invention to provide methods of treatment of malaria parasite- infected vertebrates and prophylactic methods for vertebrates exposed to malaria parasites using the aforementioned compositions in a pharmaceutically- acceptable vehicle. These and other objects, as well as the nature, scope and utilization of this invention, will become readily apparent to those skilled in the art from the following description, the drawings and the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates inhibition of proliferation of (A) cultured P.falciparum and (B) human HT-1080 cells by fluoropyrimidines. In the anti alarial experiment with parasites, incorporation of radioactivity from [G- 3 H]-hypoxanthine into nucleic acids served as a measure of parasite proliferation. Control wells incorporated 11,200 cpm of tritium from labelled hypoxanthine into precipitable nucleic acids. Each data point represents an average of two determinations. In the study of toxicity to human cells, proliferation of cells was determined directly by measuring the number of viable cells per well. Control wells showed a net increase of 350,000 cells during the 48 hour incubation. Each data point represents an average of two determinations. 5-fluoro- orotate ( ) , 5-fluorouracil (■) , 5-fluorouridine (A), and 5-fluoro-2'-deoxyuridine (♦) . Figure 2 illustrates the effects of uridine on the cytotoxicity of 5-fluoro-orotate. As in Figure 1, cells were grown for 48 hours with varying concentrations of 5-fluoroorotate. Indochina clone W-2 of P.falciparum without uridine (O) and with 1 mM uridine (•) ; Human HT-1080 cells without uridine (o) and with 1 mM uridine (■) . Half shaded symbols represent overlapping data points. Figure 3 illustrates time-dependant changes in plasma 5-fluoroorotate concentration following single intraperitoneal injections of 5-fluoro-orotate at 0.2 mg/kg (■) , 1 mg/kg (♦) , or 5 mg/kg (A), TWO mice were used at each dosage level. At each time point, duplicate 200 μl samples of blood were drawn and analyzed for 5-fluoro-orotate concentration. Figure 4 illustrates the effect of 5-fluoro¬ orotate treatment on blood parasitemia. Mice infected with P. voelii on day 0 in experiments 1 and 2 were treated with (A) 0.2 mg/kg 5-fluoro-orotate, (B) 1 mg/kg, or (C) 5 mg/kg every 4 hours for three days. Control mice (O, •, respectively) , received no drug. Open symbols represent treatment without uridine (experiment 1: O, D , φ , Δ ) , and filled symbols represent animals also treated with uridine (experiment 2: •, ■, ♦, A). Animals were treated with 5-fluoro¬ orotate on days 3 to 6. Animals were also treated with uridine in experiment 2 on days 3 to 9. Figure 5 illustrates the survival rate of mice infected with P.yoelii and treated with 5-fluoro- orotate, alone or in combination with uridine. Mice were treated with (A) 0.2 mg/kg 5-fluoro-orotate, (B) 1 mg/kg, or (C) 5 mg/kg. Control mice received no 5-fluoro-orotate (O, •, respectively) . Open symbols represent treatment without uridine (experiment 1: O, D , Δ ) - and closed symbols represent animals also receiving uridine (experiment 2: #, ■, ♦, ), Figure 6 illustrates the weight changes in mice receiving 5 mg/kg of 5-fluoro-orotate without ( Δ ) or with (A) uridine. The pyrimidine analogue was administered on days 3 to 6. The pyrimidine nucleoside was given to mice in experiment 2 on days 3 to 9. Data points represent mean weights of mice that remained alive during the course of experiments 1 and 2 (see Figure 5C) . Error bars represent standard deviations from the mean. DETAILED DESCRIPTION OF THE INVENTION The anti-malarial prophylactic and therapeutic compositions of this invention contain, inter alia, one or more pyrimidine analogues known to inhibit pyrimidine, and therefore nucleic acid, biosynthesis, and which as a result, are lethal to malaria-causing Plasmodium parasites. Such pyrimidine analogues, at certain dosage levels, can also be toxic to host vertebrates harboring the malaria parasite. Therefore, the anti-malarial compositions of this invention can also contain, if necessary, a compound that will "rescue" the host vertebrate from the toxic effects of the pyrimidine analogues. Included among such "rescue" compounds are normal pyrimidine bases or nucleosides. Such normal pyrimidine bases or nucleosides rescue the host vertebrate, but not the parasites, from toxic effects of pyrimidine analogues by virtue of the fact that vertebrates, but not Plasmodium parasites, possess the "salvage" pathway that allows the utilization of preformed pyrimidine bases or nucleosides. By this means, the host, but not malaria parasites, can be caused to by-pass the toxic affects of the blockade of caused to by-pass the toxic affects of the blockade of pyrimidine biosynthetic pathways caused by the administration of pyrimidine analogues. The £ le novo pathway for the biosynthesis of the pyrimidine nucleotides required for RNA synthesis in both vertebrates and malaria parasites is shown below: Carbamylphosphate + Aspartate -> N-carbamoyl aspartate -HOH -it dihydroorotate dehydrogenase _. Orotate Dihydroorotate phosphoribosyl- pyrophosphate (PRPP) Orotidylate -C0 2 , decarboxylase Uridylate (UMP) +ATP Uridine diphosphate (UDP) +ATP Uridine triphosphate (UTP) amination Cytidme t Ψriphosphate (CTP) As noted above, vertebrates, but not malaria parasites, are capable of producing pyrimidine nucleotides from pyrimidine bases and nucleosides by SUBSTiTuϊci "salvage" pathways. These pathways include: (a) generation of uridylate (UMP) from uridine plus ATP by uridine-cvtidine kinase; (b) production of UMP from uracil plus PRPP by uracil phosphoribosyl transferase; (c) synthesis of uridine from uracil plus ribose-i-P by uridine phosphorylase. (d) deamination of cytidine by cytidine deaminase to produce uridine; (e) generation of CMP from cytidine plus ATP by uridine-cvtidine kinase; and (f) generation of CTP from cytidine-5'- monophosphate (CMP) by consecutive transfers of phosphate from ATP, with the intermediate formation of cytidine-5*-diphosphate, in reactions catalyzed by cytidylate kinase and nucleoside diphosphate kinase. As noted above, Plasmodium parasites do not have a salvage pathway, and consequently cannot use preformed pyrimidine bases or nucleosides for RNA syntheses. Such parasites must use the de novo pathway shown above. Thus, it has been discovered that an effective inhibitor of de novo pyrimidine biosynthesis also inhibits the proliferation of Plasmodium parasites. Malarial parasites utilize orotate more efficiently than uracil and uridine for RNA synthesis. Thus, it has been discovered that orotate analogues are particularly suitable for blocking de novo synthesis of pyrimidine nucleotides from orotate in malarial parasites. Suitable orotic acid analogues include 5-fluoro-orotic acid, 5-nitro-orotic acid, 5-bromo- orotic acid, 5-thio-orotic acid, 5-diazo-orotic acid, 5-aza-orotic acid, 5-cyano-orotic acid, 5-ethynyl- orotic acid, 5-mono, di-, and tri-fluoromethyl-orotic acid, 5-hydroxymethyl-orotic acid, 5-thiomethyl-orotic acid, esters and amides of the aforementioned orotic acid analogues, O-acyl and N-acyl derivatives of orotic acid and the aforementioned orotic acid analogues, and their cis and trans-5.6-dihydro counterparts. 5-Fluoro-orotic acid and its trans-5,6-dihydro counterparts are particularly preferred. Throughout the specification, the terms "orotate" or "orotic acid" will be used interchangeably; the former represents the salt form of the latter that will be present at physiological pH values, i.e., above about 7.4. In vertebrate cells, and likely in parasite cells, 5-fluoro-orotate is metabolized to 5-fluoro-uridylate and thence to 5-fluoro-cytidylate. 5-Fluoro-uridylate and most of its metabolic products accumulate in target cells because they are phosphate esters that cannot diffuse out of the cell [Wilkinson, D.S., et al.. Cancer Res.. 36:4032 (1976)]. Further transformation of 5-fluoro-uridylate is analogous to the metabolism of uridylate, with one major exception: 5-fluoro-2'- deoxy-uridylate is a potent enzyme-activated inhibitor of thy idylate synthesis, and thus an inhibitor of DNA synthesis [Heidelberger, C. , et ai. , Adv. Enzymol.. 54:57 (1983)]. While this is a very likely explanation for the toxic effects of 5-fluoro-orotate, it is not the only possibility; 5-fluoro-pyrimidine nucleoside triphosphates, i.e., 5-F-UTP and 5-F-CTP, are incorporated into RNA, producing a non-functional analogue of RNA [Glazer, R. , et aJL. , Mol♦ Pharmacol.. 17:279 (1980)], and to a lesser extent are also incorporated into DNA, producing a non-functional DNA species [Kufe, D. , et al. , J. Biol. Chem.. 256:8885 (1981)]. Trans-5-fluoro-5 ,6-dihydroorotate (tFDHO) will interact with dihydroorotate dehydrogenase and be converted to 5-fluoro-orotate inside the parasite. In addition, tFDHO will be hydrolyzed by dihydroorotase to the fluorinated analogue of carbamyl-aspartate; this analogue will be converted to threo-3-fluoro-aspartate r an amino acid analogue itself known to have cytotoxic actions [Stern, A.M., et al., J. Med. Chem.. 25:544 (1982)]. As malarial parasites do not effectively incorporate exogenous aspartate [Sherman, I.W., Microbiol. Rev.. 43:453 (1979)], parasites will remain vulnerable to tFDHO. tFDHO is not available commercially. However, it can be synthesized by stereospecific enzymatic reduction of 5-fluoro-orotate using Z.oroticum dihydroorotate dehydrogenase and NADH, followed by purification by anion exchange chromatography. A 500 MHz proton NMR of a pure sample prepared by the inventor using this method was in complete agreement with the expected structure. The 5-H resonates at 5.43 ppm and the 6-H at 4.53 ppm. The 5-H to F geminal- coupling constant is 47 Hz. The 6-H to F vicinal coupling constant is 13 Hz. Treatment of tFDHO with bacterial dihydroorotate dehydrogenase and NAD * results in reversion to 5-fluoro-orotate: 5-fluoro-orotate L-trans-5-fluoro-5,6- dihydroorotate The interconversions between these two analogues can be followed on a Pharmacia FPLC system using a mono-Q- column. Si sTrruTg βHE r The prophylactic and therapeutic compositions of this invention can also contain, as discussed above, a compound or compounds such as one or more normal pyrimidine bases or nucleosides that selectively "rescue" the host vertebrate, but not the malaria parasite, from the toxic effects of the aforementioned orotate analogues by saturating the pool of pyrimidine nucleotides with non-substituted (e.g., non- fluorinated) metabolites. Suitable pyrimidine bases or nucleosides include uracil, uridine, cytosine, cytidine, deoxycytidine, thy ine, and deoxythymidine. Uridine is particularly preferred. The pyrimidine bases and nucleosides, and pyrimidine analogues other than tFDHO, that can be used in practicing this invention, are available commercially (Sigma Chemical Co., St. Louis, MO 63178) . It is not always necessary to rescue the host vertebrate from the toxic effects of a pyrimidine analogue. For example, mild cases of malaria parasitemia may be treated by administering doses of a pyrimidine analogue adequate, particularly in combination with the host's own defense systems (e.g., immune system) , to inhibit the proliferation of the parasites, but insufficient to be toxic to the host's own cells (see Example 8, Figures 4A and 4B) . Several types of in vitro experiments can be used to screen compositions for effectiveness -in practicing this invention: 1. Effects on parasite viability of orotate analogues alone or in combination with normal pyrimidine bases or nucleosides, or on the uptake of radioactive precursors of nucleic acid biosynthesis, e.g., [G-3-H]-hypoxanthine, can be tested on cultures of Plasmodium parasites, maintained according to Trager, et al. [Trager, W. , et al., Science. 193:673-5 (1976)] and Haynes, et al. [Haynes, J.D., et al.. Nature, 263:767-9 (1976)]. The in vitro anti-malarial activity of orotate analogues can be determined side- by-side with established anti-malarial drugs such as chloroquine. Different clones of Plasmodium can also be used as test malaria parasites, e.g., chloroquine- sensitive D6 clone from Sierra Leone and a chloroquine- resistant W2 clone from Indochina [Oduola, A.M.J., et al.. Exp. Parasitol.. 66:86-95 (1988)]. 2. Effects of orotate analogues on cell viability and the ability to synthesize nucleic acids from radioactive precursors, and the rescuing effects of normal pyrimidine bases or nucleosides or amino acid derivatives such as histidinol, can be tested in human- derived tissue culture cell lines. Human HT-1080 human sarcoma cells [Rusheed, S., et al. , Cancer. 33:1027-30 (1974)], human diploid IMR-90 cells [Nichols, W.W., et . al.. Science. 196:60-3 (1977)], human cervical sarcoma HeLa S3 cells [Puck, T.T., et al. , J. Exp. Med. , 103:273-84 (1956)], HL-60 human myeloid leukemia cells [Collins, S.J., et al. , Nature. 270:347-9 (1977)], and mouse leukemia L-1210 cells [Moore, G.E., J. Nat. Cancer Inst.. 36:405-21 (1966)] are particularly suitable for screening purposes, but those skilled in the art will know of other mammalian cell lines suitable for carrying out such screening tests. The growth medium most suitable for each cell line can be determined by reference to the publications cited above: briefly, HT-1080 cells are maintained in Eagle's Minimal Essential Medium (EMEM) supplemented with 5% fetal bovine serum (FBS) and 2 mM L-glutamine; IMR-90 cells are grown in EMEM supplemented with 10% FBS, 10 mM Hepes buffer, 0.21% NaHC0 3 , and 2 mM L- glutamine. HeLA S3 cells are grown in EMEM plus 5% FBS, 20 mM Hepes, 0.21% NaHC0 3 and 2 mM L-glutamine. HL-60 cells are grown in EMEM plus 10% FBS, 15 mM Hepes, 0.21% NaHC0 3 , 2 mM L-glutamine, and 1 mM sodium pyruvate. L-1210 cells are maintained in Dulbecco's medium [Stern, A.M., et ajL. , Cancer Res. , 44:5614-8 (1954)]. Toxicity of pyrimidine analogues to cultured human cells is determined as follows. Mammalian cells are seeded into culture plate wells, and growth medium is added. The following day, fresh culture medium containing the appropriate pyrimidine analogues is added to the wells, and the plates incubated for a period of time and at a temperature appropriate to the cell line and the experimental requirements. Thereafter, the number of cells in each well is determined. Cells that attach to culture plates (e.g., HT-1080, IMR-90, HeLA S3 cells) are dislodged by trypsinization in the presence of a heavy metal chelator, e.g. , EDTA, isolated by centrifugation at low speed (e.g., 300 x g) , washed with salt buffer (e.g., phosphate-buffered saline, PBS) , and viability determined by exclusion of a vital stain, such as trypan blue. Cells that grow in suspension (e.g. , HL-60 and L-1210 cells) are transferred to centrifuge tubes, pelleted at low speed, washed, and the viability determined as above. It is convenient to express susceptibility of cells by an IC 50 concentration, that is, the concentration of drug that kills 50% of the cells. 3. Effects of pyrimidine analogues alone or in combination with normal pyrimidine bases or nucleosides or with amino acid derivatives can be tested in malaria parasite-infected erythrocytes. Varying concentrations of pyrimidine analogues in culture medium are added to individual wells of microtitre plates [Desjardins, R.E. et al. , Antimicrob. Aσents Chemotherap.. 16:710-18 (1979)]. Parasitemic erythrocytes in culture medium are added to each well. Plates are incubated at suitable temperatures, e.g., about 37"C, for a suitable period, e.g., from about 1 hour to about 72 hours, under an atmosphere containing both C0 2 and 0 2 . Finally, a tracer concentration of a radioactive precursor of nucleic acid synthesis, e.g., [G- 3 H]- hypoxanthine, is added to each well, and the incorporation of the precursor into nucleic acids determined according to Desjardin, et al. 1979 supra. As an alternative to adding a radioactive precursor of nucleic acid biosynthesis, the end point for determining the effects of added drugs can be the incorporation of a radioactive amino acid, e.g., [U- C]-isoleucine, into parasite protein. Additionally, parasite-infected and treated erythrocytes can be smeared on microscope slides, stained with, e.g. , Giemsa stain, and the ratio of infected to non-infected erythrocytes determined. Several types of in. vivo experiments in intact vertebrates can be used to test the effectiveness in vivo of the anti-malarial compositions of this invention. In one in vivo test system, dosage regimens for pyrimidine analogues are estimated by determining the pharmacokinetics of the drugs. Normal and malaria parasite-infected animals (preferably mice, but other rodents can be used) are injected once (preferably intraperitoneally, but subcutaneous or intravenous administration is also suitable) with the drug at various doses, e.g, from 0 to about 10 mg/kg body weight, preferably from about 0.2 to about 5 mg/kg body weight. At various time points (preferably from about 3 to about 180 minutes) , blood samples are drawn from the animals and the amount of the drug in the plasma fraction determined as described in Example 7 below. The concentration of drug is plotted as a function of time for each drug dosage. From this data three important items of information are determined: (a) the time of peak plasma drug concentration at each dosage; (b) the half-life (t*j) of the drug in the circulation at each dosage; and (c) drug dosages and frequency of administration of the drug that would maintain a therapeutically-useful concentration of the drug in the patient's circulation for a suitable length of time. A second in vivo test system can be used to determine if repeated administration of the pyrimidine analogue would have safe anti-malarial activity. In this test system, groups of animals are infected with malaria parasites. At a time when blood parasitemia is reached, the animals are injected with saline alone (control) or with various concentrations of one or more pyrimidine analogues alone or together with one or more rescuing pyrimidine bases or nucleosides at a single concentration, at intervals, over a period of several days. In order to determine the prophylactic effectiveness of the rescuing pyrimidine base or nucleoside, the animals are pretreated with such a base or nucleoside prior to the administration of the pyrimidine analogue. Anti-malarial activity of the treatments is estimated by determining blood parasitemia on the animals at appropriate times. The safety of the treatments is estimated by monitoring animals for weight loss and diarrhea, as these are early symptoms of pyrimidine analogue toxicity [Houghton, J. A., et al., Cancer Res.. 39:2406-13 (1979) ]. The composition of this invention can be administered in any appropriate pharmacological vehicle for oral or parenteral administration. They can be administered by any means that provides prophylaxis and/or therapy to humans and other vertebrates. The dosage administered will be dependent upon the age, health and body weight of the recipient, kind of concurrent treatment, if any, and the nature of the effect desired. The composition can be employed in dosage forms such as tablets, capsules, powder packets ' , or liquid solutions, suspensions or elixirs for oral administration, and sterile liquid for formulations such as solutions or suspensions for parenteral use. Materials such as anti-oxidants, viscosity stabilizers and the like may be added, if necessary, to such dosage forms. In order that those skilled in the art can more- fully understand this invention, the following examples are set forth. These examples are given solely for purposes of illustration, and should not be considered as expressing limitations unless so set forth in the appended claims. Example 1 Anti-Malarial Activity of 5-Fluoro-pyrimidines Against P. falciparum Fluoropyrimidines, dispersed in 25 μl of culture medium, were added to individual wells of a 96-well microtitre plate. Human erythrocytes with 0.25-0.5% parasitemia (clone W2 of P.falciparum_) were added to each well in 200μl of culture medium to give a final hematocrit of 1.5%. Plates were incubated at 37"C for 48 hours under 5% C0 2 -5% 0 2 . Finally, the incorporation of 0.5 μCi of [G- 3 H]hypoxanthine (1 Ci/mmol) into nucleic acids in each well was determined; this served as a measure of parasite proliferation. Control wells incorporated 11,200 cpm of 3 H into precipitable material. As shown in Figure 1A, 5-fluoro-orotate showed potent antimalarial activity against the Indochina clone of P.falciparum (IC 50 = 6.0 r»M) ; 5-fluoro-uracil (IC 50 = 12 μM) , 5-fluoro-uridine (IC 50 = 32 μM) and 5-fluoro-2'- deoxyuridine (IC 50 = 100 μM) were much less effective. Example 2 Comparison of the In-vitro Anti-Malarial Activity of 5-Fluoro-orotate with That of Conventional Anti-Malarial Drugs Using P. falciparu clones Using the experimental system described in Example 1 above, the anti-malarial activity of 5-fluoro-orotate against the Indochina and Sierra Leone clones of P.falciparum was compared to that of chloroquine, quinine, pyrimethamine and sulfadoxine. As shown in Table 1 below, 5-fluoro-orotate was from about 14 to over 4,000 times more effective against the Indochina W2 clone (chloroquine-resistant) than were conventional anti-malarial drugs. Against the Sierra Leone D6 clone of P.falciparum (chloroquine- sensitive strain) , 5-fluoro-orotate was a more- effective anti-malarial than all but the highly toxic (to mammalian cells as well) pyrimethamine. Table 1 Comparison of Inhibitory Activity of 5-Fluoro-orotate and Conventional Anti-Malarial Drugs Against Plasmodium falciparum Clones * Numerical values show mean ± S.D. of five independent drug response curves. * Molar indices illustrate jLn vitro equimolar activities of 5-fluoroorotate relative to conventional drugs. For example, 5-fluoroorotate is 21 times more active than chloroquine against the multi-drug-resistant Indochina clone and 1.6 times more active than chloroquine against the chloroquine-sensitive Sierra Leone clone. Example 3 Toxicity of 5-Fluoro-Orotate Against P. falcipar-um Determined bv Three In Vitro Test Methods The chloroquine-sensitive Sierra Leone clone of P.falciparum was cultured in erythrocytes as in Example 1 above. In one method of determining the toxicity of 5-fluoro-orotate, [G- 3 H]-hypoxanthine uptake was used as an indicator of parasite proliferation, according to the procedure of Example 1 above. In a second method, the increase in parasitemia was determined directly by smearing infected erythrocytes on microscope slides, staining with Giemsa stain, and determining the ratio of infected to non-infected erythrocytes. In a third method, parasite-infected erythrocytes were incubated with [U- 14 C]-isoleucine (0.5 μCi; 0.33 Ci/mmol) , and the amount of radioactivity incorporated into precipitable proteins determined. Table 2 Test Method IC^. nM Hypoxanthine uptake 2.2 Light microscopy 2.5 Isoleucine uptake 4.7 Table 2 above shows that all three test methods yielded similar IC 50 values. Therefore, each of these three tests is a valid measure of 5-fluoro-orotate toxicity to malarial parasites in cultures. Example 4 Effects of Pyrimidine Analogues on Mammalian Cells Proliferation of human fibrosarcoma cells (HT- 1080) was determined directly by measuring the number of viable cells per culture well. HT-1080 cells were seeded into 6-well culture plates at a density of 50,000 cells per 9.6 cm 2 well. Each well contained 2.5 ml of growth medium. The following day, fresh culture medium containing the appropriate fluoropyrimidine was added to the wells, and the plates were incubated at 37 β C for 48 hours in a 5% C0 2 incubator. Thereafter, plates were washed with Ca 2+ -Mg 2+ -free phosphate-buffered saline (PBS-CMF, 136 mM NaCl, 2.7 mM KC1, 8 mM Na 2 HP0 4 , 1.5 mM KH 2 P0 4 ) , and then treated with 1 ml of 0.05% trypsin and 0.02% EDTA in PBS-CMF. After 1 minute, the detached cells were suspended in 1.0 ml of EMEM and collected by centrifugation at 300 x g for 3 minutes. Cell pellets were suspended in 1 ml of PBS-CMF, and a 0.5 ml portion of this suspension was mixed with 0.4 ml of PBS-CMF and 26 0.1 ml of Trypan blue solution (0.5% of the dye in 0.85% saline). The concentrations of viable cells were determined in a hemocytometer. As shown Figure IB, it required about 10 μM of 5-fluoro-orotate to cause a 50% inhibition of these human cells as compared to 6 nM to achieve the same results with P.falciparum (Figure 1A) , indicating that these human cells are less sensitive to the analogue than are the parasites. The HT-1080 mammalian cell line was less vulnerable to 5-fluoro-orotate than to the commonly-used anti-cancer drugs, 5-fluoro-uracil (IC 50 = 2μM) , 5-fluoro-uridine (IC 50 = 30 nM) and 5-fluoro-2'-deoxy-uridine (IC 50 - 10 nM) (Figure IB), indicating that orotate analogues are preferable to uracil or uridine analogues in the prophylactic and therapeutic compositions of the invention. Example 5 Comparison of Inhibitory Activity of 5-Fluoro-Orotate Against Different Mammalian Cell Lines - Rescue Effect of Uridine Using the test system of Example 4 above, the toxicity of 5-fluoro-orotate was tested against a battery of four human cell lines and a rapidly dividing mouse cell line. As shown in Table 3, even though the IC 50 values ranged between 0.9 and 10 μM, none of the mammalian cell lines approached the vulnerability of malarial parasites (IC 50 = 6 nM, Figure 1A) to this pyrimidine analogue. In five mammalian cell lines, added 1 mM uridine reduced the inhibitory effect of 5-fluoro-orotate on cells (Table 3, right column). Depending on the cell line, the IC 50 values for 5-fluoro-orotate were 2 to 5 times higher in the presence of 1 mM uridine than in its absence. These data substantiate the inventive concept that uridine can be used in a prophylactic or therapeutic anti-malarial composition to rescue the host vertebrate from the toxic effects of the pyrimidine analogue, 5-fluoro-orotate. Table 3 Comparison of Inhibitory Activity of 5-Fluoro-Orotate Against Different Mammalian Cell Lines in the Absence and Presence of Uridine Example 6 Effects of Uridine on the In Vitro Cytotoxicity of 5-Fluoro-Orotate As in Examples 1 and 4 above, malaria parasites (Indochina clone W-2 of P.falciparum) and human HT-1080 cells were grown for 48 hours with varying concentrations of 5-fluoro-orotate in the absence and presence of 1 mM uridine. As shown in Figure 2, the cytotoxicity of 5-fluoro-orotate to human HT-1080 cells was decreased 5-fold by simultaneous administration of 1 mM uridine. In contrast, uridine had no effect on the cytotoxicity of 5-fluoro-orotate towards malarial parasites. Example 7 Phar acokinetics of 5-Fluoro-orotate in Mice Pairs of Swiss white mice (Charles River Labs, MA) were injected intraperitoneally with 200 μl of [2- C]- 5-fluoro-orotate in saline (55 μCi/μmol) . Single injections of the drug were made at dosages of 0.2, 1 and 5 mg/kg body weight. At time points ranging from about 3 to about 180 minutes, two 200 μl blood samples were drawn from the tail veins of the mice, and the amount of 5-fluoro-orotate present in the plasma determined, as described below. Blood samples were immediately diluted in 100 μl of cold saline, and centrifuged in a desk top Eppendorf centrifuge for 1 minute to separate the plasma fraction from blood cells. Cell pellets were washed with 100 μl of saline, centrifuged, and the supernatant fractions mixed with plasma fractions. In order to determine the 5-fluoro-orotate concentrations of the diluted plasma fractions, the radioactive content of half the samples was determined by liquid scintillation spectrometry. The remaining samples were chromatographed on a Pharmacia FPLC system using a Mono Q anion-exchange column. Ninety minutes after 5-fluoro-orotate injection, the radioactive counts from the plasma fraction co-migrated with a non-radioactive 5-fluoro¬ orotate standard confirming that radioactivity in the plasma fraction was due to 5-fluoro-orotate and not some secondary metabolite of the experimental drug. As shown in Figure 3, at all dosages tested, plasma 5-fluoro-orotate concentrations peaked within about 20 minutes. Thereafter, the drug was lost from the circulation with a ~ of about 90 minutes. With a single dose of 5 mg/kg, plasma concentrations of the drug reached values as high as about 30 μM, but rapidly dropped to below 10 μM. At a dose of 0.2 mg/kg, the drug concentration did not exceed about 2 μM, and dropped below 0.5 μM within 60 minutes. Less than 10% of the total circulating radioactivity was associated with blood cells. The pharmacokinetic profile of plasma 5-fluoro-orotate in mice infected with P.yoelii (10% parasitemia) , tested at 1 mg/kg, was essentially the same " as that of uninfected mice. These data suggest that a dose of about 0.2 to about 5 mg/kg administered every 4 hours would maintain plasma 5-fluoro-orotate at about 0.1 to about 1 μM under in vivo conditions. As shown in Example 1 above, P.falciparum exposed to 0.1 to 1 μM 5-fluoro-orotate for 48 hours ceased to incorporate hypoxanthine and ceased to proliferate. In addition, as shown in Example 4 above, these concentrations of the drug were not toxic to rapidly dividing mammalian cells in culture. Example 8 In Vivo Effects of Therapeutic Compositions on Parasite-Infectivitv and Host Toxicity in Mice Swiss white mice (25-30 g) were divided into groups of five. On day 0, each mouse was infected by intraperitoneal injection of 10 5 erythrocytic forms of P.yoelii. Starting on day 3, when the blood parasitemia had reached between 5 and 12%, the mice were injected intraperitoneally every 4 hours for three consecutive days with 200 μl of various formulations. In experiment 1, three groups of mice received 0.2, 1, or 5 mg/kg of 5-fluoro-orotate per injection, respectively. An accompanying control group received saline. In experiment 2, three groups of mice received 0.2, 1, or 5 mg/kg of 5-fluoro-orotate plus 800 mg/kg of uridine in a 200 μl saline formulation. An accompanying control group received 800 mg/kg of uridine alone. In experiment 2, mice were pretreated with one injection of 800 mg/kg of uridine two hours before receiving the first injection of 5-fluoro¬ orotate. Additionally, even though treatment with the pyrimidine analogue stopped on day 6, these mice continued to receive 1500 mg/kg of uridine, three times a day, for three additional days (i.e., up to day 9). The results of these in vivo experiments showed that 5-fluoro-orotate exhibited a dose-dependent ability to suppress parasitemia in mice infected with the malaria parasite, P.yoelii. In experiments 1 and 2, mice not receiving 5-fluoro-orotate showed a rapid increase in parasitemia (Figures 4A-C) . By day 6 after infection, parasitemia levels as high as 75% were seen in those mice that had not died of the infection. In contrast, every mouse treated with the pyrimidine analogue showed a rapid decrease in parasitemia between days 3 and 6 (Figures 4A-C) . Once treatment with 5-fluoro-orotate was stopped on day 6, mice that had been treated with the lowest dose, i.e., 0.2 mg/kg, showed a return of parasitemia within 24 hours (Figure 4A) . Similarly, mice treated with 1 mg/kg of the analogue also showed a recurrence of infection, although recurrence was delayed compared to the lower dosage (Figure 4B) . Such recurring parasitemias were seen at low doses of the 5-fluoro¬ orotate in experiments l and 2. Within a period of about 14 days, the second surge of parasitemia resolved itself without the need for additional treatment with the drug (Figures 4A and 4B) , suggesting that the immune system of the mice was able to destroy parasites that had previously been weakened by the 5-fluoro¬ orotate. A dose of 5 mg/kg of 5-fluoro-orotate completely prevented this second surge of parasitemia (Figure 4C) . The anti-malarial activity of 5-fluoro-orotate was not compromised by the co-administration of uridine in experiment 2, in keeping with the in vitro results observed in Example 5 above. In experiment 1, mice that did not receive 5-fluoro-orotate all succumbed to P.yoelii. but none of the mice that received 0.2 mg/kg of the analogue perished (Figure 5A) . At higher doses, i.e., 1 and 5 mg/kg, of the analogue, there was a dose-dependent increase in mortality of mice not receiving uridine (Figures 5B and 5C, respectively) . The mice that survived showed signs of diarrhea. The mice receiving 5 mg/kg of 5-fluoro-orotate did not die of malaria; no parasites were observed in blood just prior to death. Mice receiving uridine either before or along with 5-fluoro-orotate were cured of malaria without suffering from drug toxicity. In experiment 2, mice not receiving 5-fluoro-orotate all succumbed to P.yoelii. but no mouse receiving 0.2, 1-or 5 mg/kg of the analogue perished from the malaria. In addition, no mouse had diarrhea, and even at the highest drug dose (5 mg/kg) , mice showed no weight loss (Figure 6) . Mice that received 5-fluoro-orotate subsequent to infection by P.yoelii were considered cured by the following criteria. One, for periods as long as sixty days after initial infection, no parasites were detected in blood smears of any of the 5-fluoro-orotate-treated mice. In these studies, greater than 10,000 Wright's stain treated red blood cells were inspected under the microscope. Two, when 10 6 erythrocytes from five different 5-fluoro-orotate- treated mice were injected intraperitoneally into five separate naive mice, no infections developed in the recipients. The treated mice were from the 0.2 mg/kg group, 60 days after the original infection. Three, when a standard innoculum of 10 6 P.yoelii parasites was injected into the same five 5-fluoro- orotate-treated mice, a transient parasitemia of less than 0.05% was observed between days 2 and 4; after day 4, no parasites were observed in these challenged mice. This last experiment showed that these mice were not only cured, but protected from new infections. In summary, the experiments of Example 8 demonstrate that mice infected with P.yoelii were (apparently permanently) cured of malaria by multiple doses of 5-fluoro-orotate. At low doses,- the elimination of the malarial parasite may rely on the immune system. A higher dose of 5 mg/kg body weight every 4 hours, which is required for radical elimination of malarial parasites, was tolerated only when uridine was administered in combination with 5- fluoro-orotate. The host mammal readily tolerated even the highest dose of 5-fluoro-orotate when uridine was administered either before, during or after infection with Plasmodium. These in vivo results support prophylactic and therapeutic anti-malarial uses of the compositions of the invention. The above disclosure of this invention is directed primarily to preferred embodiments and practices thereof. It will be readily apparent to those skilled in the art that further changes and modifications in the actual implementation of the concepts described herein can easily be made without departing from the spirit and scope of the invention as defined by the following claims.

Claims: I Claim: 1. An anti-malarial composition comprising (a) at least one pyrimidine analogue inhibitor of nucleic acid biosynthesis in malaria parasites, and (b) at least one rescuing pyrimidine base or nucleoside that can be used by a host vertebrate infected with malaria parasites, but not by malaria parasites themselves, to synthesize nucleic acids. 2. A composition of claim 1 wherein the pyrimidine analogue is 5-fluoro-orotic acid, 5-nitro- orotic acid, 5-bromo-orotic acid, 5-thio-orotic acid, 5-diazo-orotic acid, 5-aza-orotic acid, 5-cyano-orotic acid, 5-ethynyl orotic acid, 5-mono, di, and tri- fluoro-methyl-orotic acid, 5-hydroxymethyl-orotic acid, 5-thiomethyl-orotic acid, an ester or amide thereof, O-acyl or N-acyl derivatives thereof, or a cis or trans-5.6-dihydro counterpart of any of the foregoing compounds. 3. A composition of claim 1 wherein the pyrimidine base or nucleoside is uracil, uridine, cytosine, cytidine, thymine, deoxythymidine or deoxycytidine. 4. A composition of claim 1 wherein the pyrimidine analogue is 5-fluoro-orotic acid and the pyrimidine nucleoside is uridine. 5. A composition of claim 1 wherein the pyrimidine analogue is trans-5-fluoro-5,6-dihydro orotic acid and the pyrimidine nucleoside is uridine. 6. A composition of claim 1 wherein the pyrimidine analogue is a mixture of 5-fluoro-orotic acid and trans-5.6-dihvdro-5-fluoro-orotic acid and the pyrimidine nucleoside is uridine. 7. A composition of any one of claims 1-6, inclusive, comprising an anti-malarial effective amount of a pyrimidine analogue plus a host rescuing amount of a pyrimidine base or nucleoside in a pharmaceutically acceptable vehicle. 8. A method for treating a vertebrate exposed to malaria-causing parasites comprising administering to the vertebrate a composition comprising (a) an anti- malarial effective amount of at least one pyrimidine analogue inhibitor of nucleic acid biosynthesis, and (b) a host rescuing amount of at least one pyrimidine base or nucleoside that can be used by a host vertebrate infected with the malarial parasites, but not by the parasites themselves, to synthesize nucleic acids, in a pharmaceutically acceptable vehicle. 9. A method of claim 8 wherein the pyrimidine analogue is 5-fluoro-orotic acid, 5-nitro-orotic acid, 5-bromo-orotic, 5-thio-orotic acid, 5-diazo-orotic acid, 5-aza-orotic acid, 5-cyano-orotic acid, 5-ethynyl orotic acid, 5-mono, di, and tri-fluoromethyl-orotic acid, 5-hydroxymethyl-orotic acid, 5-thiomethyl-orotic acid, an ester or amide thereof, an O-acyl or N-acyl derivative thereof, or a cis or trans-5.6-dihvdro counterpart of any of the forementioned compounds. 10. A method of claim 8 wherein the pyrimidine base or nucleoside is uracil, uridine, cytosine, cytidine, thymine, deoxythymidine or deoxycytidine. 11. A method of claim 8 wherein the pyrimidine analogue is 5-fluoro-orotic acid and the pyrimidine nucleoside is uridine. 12. A method of claim 8 wherein the pyrimidine analogue is trans-5-fluoro-5,6-dihydro orotic acid and the pyrimidine nucleoside is uridine. 13. A method of claim 8 wherein the pyrimidine analogue is a mixture of 5-fluoro-orotic acid and trans-5-fluoro-5 ,6-dihydro orotic acid and the pyrimidine nucleoside is uridine. 14. A method of claim 8 wherein the composition is administered prophylactically. 15. A method of claim 14 wherein the composition is administered orally, parenterally or intranasally. 16. A method of claims 8 wherein the composition is administered therapeutically. 17. A method of claim 16 wherein the composition is administered orally, parenterally, or intranasally. 18. An anti-malarial composition comprising at least one pyrimidine analogue inhibitor of nucleic acid biosynthesis in a pharmaceutically acceptable vehicle. 19. A composition of claim 18 wherein the pyrimidine analogue is 5-fluoro-orotic acid, 5-nitro- orotic acid, 5-bromo-orotic acid, 5-thio-orotic acid, 5-diazo-orotic acid, 5-aza-orotic acid, 5-cyano-orotic acid, 5-ethynyl orotic acid, 5-mono, di, and tri- fluoro-methyl-orotic acid, 5-hydroxymethyl-orotic acid, 5-thiomethyl-orotic acid, an ester or amide thereof, O-acyl or N-acyl derivatives thereof, or a cis or trans-5,6-dihydro counterpart of any of the foregoing compounds. 20. A composition of claim 18 wherein the pyrimidine analogue is 5-fluoro-orotic acid. 21. A composition of claim 18 wherein the pyrimidine analogue is trans-5-fluσro-5.6-dihydro- orotic acid. 22. A composition of claim 18 wherein the pyrimidine analogue is a mixture of 5-fluoro-orotic acid and trans-5-fluoro-5.6-dihydro-orotic acid. 23. A method for treating vertebrates exposed to malaria-causing parasites comprising administering to the vertebrate an amount of a composition comprising at least one pyrimidine analogue inhibitor of nucleic acid biosynthesis that is effective in inhibiting parasite growth, but is without substantial deleterious effect on the host vertebrate, in a pharmaceutically acceptable vehicle. 24. A method of claim 23 wherein the pyrimidine analogue is 5-fluoro-orotic acid, 5-nitro-orotic acid, 5-bromo-orotic, 5-thio-orotic acid, 5-diazo-orotic acid, 5-aza-orotic acid, 5-cyano-orotic acid, 5-ethynyl orotic acid, 5-mono, di, and tri-fluoromethyl-orotic acid, 5-hydroxymethyl-orotic acid, 5-thiomethyl-orotic acid, an ester or amide thereof, an O-acyl or N-acyl derivative thereof, or a cis or trans-5.6-dihydro counterpart of any of the forementioned compounds. 25. A method of claim 23 wherein the pyrimidine analogue is 5-fluoro-orotic acid. 26. A method of claim 23 wherein the pyrimidine analogue is trans-5-fluoro-5.6-dihydro orotic acid. 27. A method of claim 23 wherein the pyrimidine analogue is a mixture of 5-fluoro-orotic acid and trans-5-fluoro-5.6-dihydro orotic acid. 28. A method of claim 23 wherein the composition is administered prophylactically. 29. A method of claim 28 wherein the composition is administered orally, parenterally or intranasally. 30. A method of claim 23 wherein the composition is administered therapeutically. 31. A method of claim 30 wherein the composition is administered orally, parenterally or intranasally. 32. An anti-malarial composition comprising at least one pyrimidine analogue inhibitor of nucleic acid biosynthesis in a pharmaceutically-acceptable vehicle, the pyrimidine analogue being present in an amount effective to inhibit parasite proliferation but without substantial deleterious effect on the host vertebrate. 33. A composition of claim 32 wherein the pyrimidine analogue is 5-fluoro-orotic acid, 5-nitro- orotic acid, 5-bromo-orotic acid, 5-thio-orotic acid, 5-diazo-orotic acid, 5-aza-orotic acid, 5-cyano-orotic acid, 5-ethynyl orotic acid, 5-mono, di, and tri- fluoro-methyl-orotic acid, 5-hydroxymethyl-orotic acid, 5-thiomethyl-orotic acid, an ester or amide thereof, O-acyl or N-acyl derivatives thereof, or a cis or trans-5.6-dihydro counterpart of any of the foregoing compounds. 34. A composition of claim 32 wherein the pyrimidine analogue is 5-fluoro-orotic acid. 35. A composition of claim 32 wherein the pyrimidine analogue is trans-5-fluoro-5,6-dihydro- orotic acid. 36. A composition of claim 32 wherein the pyrimidine analogue is a mixture of 5-fluoro-orotic acid and trans-5-fluoro-5.6-dihydro-orotic acid. 37. The use of at least one pyrimidine analogue inhibitor of nucleic acid biosynthesis in malaria parasites and at least one pyrimidine base or nucleoside that can be used by a host vertebrate infected with the malarial paarasites, but not by parasites themselves, to synthesize nucleic acids, for the manufacture of a medicament for prophylactic or therapeutic treatment of malaria in vertebrates. 38. The use of claim 37 wherein the pyrimidine analogues comprise one of 5-fluoro-orotic acid, 5-nitro-orotic acid, 5-bromo-orotic acid, 5-thio-orotic acid, 5-aza-orotic acid, 5-cyano-orotic acid, 5-ethynyl orotic acid, 5-mono, di, and tri-fluoro-orotic acid, 5-hydroxymethyl-orotic acid, 5-thiomethyl-orotic acid, esters and amides of the aforementioned orotic acid analogues, O-acyl and N-acyl derivatives of orotic acid and the aforementioned orotic acid analogues, or their trans-5,6-dihydro counterparts. 39. The use of claim 37 wherein the pyrimidine base or nucleoside comprise uracil, uridine, cytosine, cytidine, thymine, deoxythymidine and deoxycytidine. 40. The use of claim 37 wherein the pyrimidine analogue is 5-fluoro-orotic and the pyrimidine nucleoside is uridine. 41. The use of claim 37 wherein the pyrimidine analogue is trans-5-fluoro-5.6-dihydro orotic and the pyrimidine nucleoside is uridine. 42. The use of claim 37 wherein the pyrimidine analogue is 5-fluoro-orotic acid and trans-5,6-dihydro- 5-fluoro-orotic acid and the pyrimidine nucloeside is uridine.

Inventors: RATHOD PRADIPSINH K, RATHOD, PRADIPSINH, K.
Applicants: UNIV AMERICA CATHOLIC, THE CATHOLIC UNIVERSITY OF AMERICA
Application year: 1990
Main classification: A61K
IPC codes: A61K31, A61K45, A61P33