Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2121/00—Preparations for use in therapy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2123/00—Preparations for testing in vivo

Definitions

• This invention pertains to novel radioactive antiviral compounds, with 1-(ß-D-arabinofuranosyl)-5(E)-(2-[*I]-iodovinyl) uracil, hereinafter referred to as w[*I]-IVaraU", as the prototype compound for the class of compounds designated as 1-(ß-D-arabinofuranosyl)-5(E)-(2-[*X]-halogenovinyl) uracil, hereinafter referred to as "[*X]-XVaraU”, and novel precursors thereof, 1-(2,3,5-tri-O-acetyl-ß-D-arabinofuranosyl)-5( Z and E) - (2-trimethylsilylvinyl) uracil, hereinafter referred to as "TMSVaraU", and processes for the preparation thereof, and uses thereof, wherein "*I” stands for a radionuclide of iodine, and *X stands for any other appropriate halogen radionu
• Yamasa Shoyu Company Ltd. has developed a group of nonradioactive antiviral compounds known as 1- (ß-D-arabinofuranosyl)-5(E)-(2-halogenovinyl) uracils (XVara ⁇ 's) and methods of preparation of same.
• halogeno hereinafter designated as "X” in the abbreviated form, includes bromo, chloro, and iodo.
• the bromo derivative known as 1- (ß-D- arabinofuranosyl)-5(E)-(2-bromovinyl) uracil, or "BVaraU", "BV-araU”, or "BVAU" is easy to synthesize, owing to the high reactivity of the halogen, bromine.
• BVaraU As an antiviral agent, BVaraU is effective against herpes virus infections of man and animals which are associated with viral-induced (deoxy) thymidine kinases.
• a list of the known Yamasa patents protecting unlabeled BVaraU as an antiviral therapeutic agent are as follows:
• Herpes simplex virus, herpes (varicella) zoster virus, cytomegalovirus, and Epstein Barr virus hereinafter referred to as "HSV”, “VZV”, “CMV”, and “EBV”, respectively, are common human herpesviruses, which significantly contribute to a number of important ailments which afflict centuries. Most often, HSV and VZV are associated with skin or mucous membrane lesions which readily lend themselves to rapid and accurate viral diagnosis, generally using standard swab/culture techniques. By contrast, target organ and life-threatening infections with these viruses often evade diagnosis, because of the difficulty in achieving access to infected tissues on which to apply the culture techniques.
• invasive testing The physician is often presented with the choice of either guessing what the patient has contracted based on symptoms and signs or obtaining a piece of deep tissue for analysis by surgical or endoscopic procedures (invasive testing).
• invasive testing Recent advances in the chemotherapy of herpes virus infections have resulted in an expansion of the need to eliminate invasive testing, along with its inherent inaccuracies, delays, and morbidity.
• invasive testing is not practical, e.g., with retinal or other deep ophthalmic infections, and for neurological complications of herpes infections such as post-herpetic neuralgia or transverse myelitis.
• Such agents are phosphorylated by HSY-specified deoxythymidine kinases, a group of herpesviral-specific enzymes, hereinafter designated as "dTK's".
• dTK's herpesviral-specific enzymes
• the first such hypothesis was published by Saito, et al [45,46], who studied HSV-specific localization with [ 14 elabeled]-2'-fluoro-5-methyl-1-ß-D-arabinosyluracil ( [ 14 C] -FMAU) . They demonstrated a high correlation between focal infection and increased [ 14 C]-FMAU uptake in brain sections.
• [ 14 C]-FMAU is phosphorylated by certain herpesviral dTK's, and was specifically concentrated in areas of infection.
• FIAC 2'-fluoro-5-iodo-1-ß-D-arabinosylcytosine
• FIAC 2'-fluoro-5-iodo-1-ß-D-arabinosylcytosine
• FIAC is known to be subject to nonspecific decomposition, with resulting loss of iodine.
• this agent is excessively toxic and can be phosphorylated and incorporated to some extent by uninfected, rapidly dividing cells.
• US Patent #4,489,052 The need for a positron or gamma-emitting radionuclide in order to make clinical diagnosis practical was discussed.
• US Patent #4,489,052 does not disclose, consider, or teach the use of [*X] -XVaraU or [*I]-IVaraU for this purpose, and was specifically limited to the use of 5-substituted-1-(2-deoxy-2-substituted-D-arabinofuranosyl) pyrimidine nucleosides. It also did not disclose, provide, or teach a method for radiolabeling of their nucleoside, or any other nucleoside, with a halogen radionuclide, but merely speculated on that possibility for their class of 5- substituted-1-(2-deoxy-2-substituted-D-arabinofuranosyl) pyrimidine nucleosides.
• Acyclovir 9-[(2-hydroxyethoxy) methyl] guanine, is a "nucleoside analogue" whose antiviral activity is dependent upon herpes virus-induced dTK's.
• Radiolabeled acyclovir was tested for its potential as a diagnostic agent, but those experiments were too insensitive to demonstrate acyclovir localization based on drug anabolism in infected tissues [47]. This may have resulted from passive uptake of acyclovir by T-minfected cells, even though the phophorylation of acyclovir is likely enhanced in viral-infected cells.
• Acyclovir has also failed as a diagnostic agent because of difficulties in producing a stable or clinically practical radionuclide label, since this compound contains no halogen in its chemical structure.
• [ 131 I]-IVdU is structurally distinct from [*I]-IVaraU.
• the former is a derivative of 2' -deoxyuridine; the latter a derivative of 1-(ß-D- arabinofuranosyl) uracil. This major difference in the sugar moieties provides the basis for the predominance of metabolic resistance of [*I]-IVaraU to cleavage in vivo .
• X is a radioisotope of iodine, selected from the group consisting of radioactive 1 23 I, 125 I, 127 I, 131 I, or, alternatively, a radiohalogen selected from the group consisting of radioactive 75 Br, 76 Br, 77 Br, 82 Br, 34 Cl, or other appropriate radionuclides which comprises: (a) converting uridine to its arabino analogue; (b) protecting the arabino sugar moiety against substitution or degradation with suitable protecting substances; (c) halogenating the protected analogue at the C5 position; (d) coupling the halogenated analogue with an appropriate compound to form a vinyl compound at the C5 position; (e) radiohalogenating the coupled compound at the terminal carbon atom of the C5-vinyl group; and (f) removing the protecting substance from the arabino sugar moiety.
• X is a radiohalogen isotope selected from the group consisting of radioactive 123 I, 125 I, 127 I, 131 I, or, alternatively, from the group consisting of 75 Br, 7 ⁇ Br, 77 Br, 82 Br, 34 C1, or other appropriate radionuclides which comprises: (a) converting uridine to its arabino analogue; (b) protecting the arabino analogue by acetylation; (c) halogenating the protected analogue at the C5 position; (d) coupling the halogenated protected analogue with trimethylsilylacetylene; (e) reducing the coupled compound to a vinyl silane; (f) radiohalogenating the reduced compound; (g) removing the acetyl groups from the arabino ring.
• radiohalogen isotope selected from the group consisting of radioactive 123 I, 125 I, 127 I, 131 I, or, alternatively, from the group consisting of 75 Br, 7 ⁇ Br, 77
• X is a radioisotope of iodine selected from the group consisting of radioactive 123 I, 125 I,- 127 I, 131 I, or alternatively, a radiohalogen selected from the group consisting of radioactive 75 Br, 76 Br, 77 Br, 82 Br, 34 Cl, or other appropriate radionuclides.
• Figure 1 illustrates in graphical format the process of the invention for synthesizing a precursor compound, 1- (2, 3, 5-tri-O-acetyl-ß-D-arabinofuranosyl)-5(Z) -(2-trimethylsilylvinyl) uracil, followed by preparation of 1-(ß-D-arabinofuranosyl)-5(E) -(2-[*I]-iodovinyl) uracil, as the prototype compound for the class of compounds designated as 1-(ß-D-arabinofuranosyl)-5(E)-(2-[*X]-halogenovinyl) uracil, wherein any halogen radionuclide is used in the process.
• FIG. 1 Trapping of [ 125 I] -IVaraU in HSV-1-infected PRK cells. A variety of HSV-1 mutants are compared demonstrating the dependence of trapping upon expression of viral dTK's.
• Figure 4 Trapping of [ 125 I] -IVaraU into HSV-1-infected PRK cells : Effects of varying inocula and times of virus exposure. These results demonstrate that at an inoculum of 1 PFU per cell, [ 125 I-] IVaraU trapping will detect growth of HSV-1 as early as 4.0 hours Figure 5. Localization of [ 123 I] -IVaraU in HSV-1-infected areas of the New Zealand White rabbit infected onto the cribriform plate.
• A A photograph of a positive scan from an animal scanned 7 days post-infection which is acutely infected in the nasopharynx and olfactory bulb.
• B Scan 7 weeks post-infection of a control animal latently, but not actively infected. Olfactory bulb necrotic but no virus present. Similar appearance to an uninfected control animal.
• KOS HSV-1
• [*I] -IVaraU is taken up by infected cells at approximately one to two thousand times the concentrations observed inside normal cells treated with this agent. This highly specific targeting to infected cells is dependent upon the action of herpes virus-induced dTK's which cause the phosphorylation of the nucleoside, and in so doing, trap the resulting phosphate ester inside the cell. At our level of detection, [*I] -IVaraU is not phosphorylated and/or trapped inside of normal, uninfected cells.
• [*I] -IVaraUMP is an abbreviation for [*I] -IVaraU 5' -monophosphate, the first nucleotide product made by the herpes virus- specific enzymes known as the dTK's.
• [*I] -IVaraUMP is again phosphorylated by the same herpes protein (dTK) which (for selected herpes viruses) also displays herpes virus-specific thymidylate kinase activity that catalyzes the formation of [*I] -IVaraU 5' -diphosphate, abbreviated [*I] -IVaraUDP.
• the cell may further process the nucleotide.
• PyNP's are widely distributed human enzymes which have severely thwarted development of nucleoside antiviral agents. PyNP's quickly cleave most nucleosides and nucleotides of this class. We have discovered that PyNP's are relatively inactive against [*I] -IVaraU, owing to the unnatural sugar moiety, arabinose. PyNP's actions result in "phosphorolysis" which cleaves the nucleoside into the sugar and base components. If this activity were functional with [*I] -IVaraU, it would be converted into
• [*I] -IVaraU if any is formed, it is in insignificant quantities.
• BVaraU is also resistant to PyNP's cleavage, suggesting that all [*X] -XVaraU's will have similar targeting characteristics.
• the physician can tailor the medicine according to its use by selecting the radionuclide for optimal imaging and safety characteristics for gamma scans (for example, by selecting 123 I, 131 I, or 82 Br), vs. optimal imaging and safety characteristics for positron emission scans (for example, by selecting 123 I, 127 I, 75 Br, 76 Br, 77 Br, 82 Br, 34 Cl), vs.
• the precursor compounds named above can be reacted in the penultimate synthetic step with radiolabeled iodine, using the generally available compounds, Na 125 I, Na 123 I,and Na 131 I or, in the alternative, a less-widely used iodine radionuclide, Na 127 I, or, in the alternative, other halogen radionuclides, e.g., Na 75 Br, Na 76 Br, Na 77 Br, Na 82 Br, Na 34 Cl, or alternative salts of these radiohalogens.
• the radiopharmaceutical agents of this invention can be generated quickly in a small laboratory in a hospital's nuclear medicine department.
• the conditions are mild, standard, and easy to reproduce, and employ inexpensive and disposable equipment.
• the success of our processes has been achieved via general precursor agents that react rapidly to give exchange of halogen lor trimethylsilyl.
• Initial experiments were performed with iodine radionuclides, since 123 I, 125 I, and 131 I provide an ideal combination of clinically useful, safe with long half-life, and lethal radionuclides, respectively.
• phenyliodine (III) dichloride to effect formation of iodine monochloride as a stoichiometric source of iodine radionuclides for such reactions.
• xenon difluoride has been used to generate the mixed halogens IF, BrF, and ClF in situ, for general radiohalogenation in such reactions.
• [*I] -IVaraU was synthesized from the precursor, TMSVaraU, with iodine monochloride (ICl) produced in situ from sodium iodide and phenyliodine (III) dichloride.
• Phenyliodine (III) dichloride serves as oxidant and chlorine donor, resulting in the formation of iodine monochloride, which subsequently effects replacement of the TMS group by iodine on the vinyl side chain (at C2) with the trans (E) configuration.
• Sodium iodide (12 mg, 0.08 mMole, 1.3 eq) was added to a 3 ml reacti-vial equipped with a stir bar and wrapped in aluminum foil to protect it from light.
• the deprotected compound was found to have an R f of ⁇ 0.75.
• the methanol solution was neutralized by the careful addition of a solution of two drops of concentrated HCl in 2.5 ml of 100% ethanol and checked with pH paper, range: 6.0-8.0. The solvent was removed by evaporation. The solid remaining had a yellow colour associated with it, which could be removed to a great extent by stirring with ethyl acetate or dry ether. This treatment results in -15 mg of an off-white product containing some sodium chloride.
• the compound had 13 C nuclear magnetic resonance chemical shifts in dimethyl sulfoxide solution at ⁇ 149.17 (C2), 161.81 (C4), 110.02 (C5), 140.96 (C6), 137.06 and 84.70 (ethenyl Cl and C2), 85.29 (Cl'), 75.23 (C2'), 74.93 (C3'), 77.54 (C4'), 60.44 (C5').
• Example 1 The previous reaction (Example 1) yielded large quantities of IVaraU in the presence of sodium iodide. In order to synthesize radiolabeled material, however, the reaction required further dilution, to accomodate the small quantities of Na[*I]-I as pure radionuclide.
• One "carrier-added” product was made at low specific activity, in order to avoid altering the total concentrations of the reactants. This was accomplished by mixing a commercial sample of Na [ 125 I] -I/NaOH (2 mCi in 20 ⁇ l : specific activity 17 Ci/mg) with unlabeled Nal in approximately 1:5000 ratio prior to the reaction.
• This solution was neutralized with an equal volume of phosphate buffered physiological saline (pH 7.4), by adding the saline solution to the V-vial containing the radionuclide. Subsequently, 25 ⁇ l of spectral quality benzene was added, a.long with 0.5 mg of NaI and 1.0 mg of phenyliodine (III) dichloride. The reaction mixture was shaken vigorously and placed in the plastic safety container (which is supplied with the 122 I-sodium iodide), to shield it from light. The reaction was allowed to proceed for 15 minutes at room temperature, with frequent shaking. Two layers were visible; a dark red upper organic layer, and a slightly yellow-colored aqueous layer.
• TMSVaraU TMSVaraU was dissolved in 25 ⁇ l of benzene, and added to the V-vial using a glass capillary pipette.
• the vial was returned to the safety container and shaken every 15 minutes for 1.5 hours.
• 0.5 ml of 5% aqueous bisulfite was added to the reaction vial.
• additional benzene was added to facilitate the extraction process.
• the contents were removed with a pasteur pipette, and the layers allowed to separate.
• the benzene layer was added to a column of dry silica gel in the terminal portion of a glass Pasteur pipette.
• the aqueous bisulfite layer was extracted with benzene, and the benzene was added to the column.
• the column was washed with one column volume of dichloromethane.
• the product was then eluted with dichloromethane:ethyl acetate (2:1) mixture, and collected in one vial.
• Solvent was removed by passing a stream of N 2 gas over the vial.
• a small piece of elemental sodium was added to 1 ml of HPLC grade methanol to form a sodium methoxide solution. 0.5 ml of this solution was added to the dried compound. After 15 minutes, the progress of the deprotection reaction was checked using silica coated TLC plates against a standard.
• the running solvent was chloroform: methanol, (8:2).
• the deprotected compound has an R f of ⁇ 0.75.
• the solution was not neutralized, and the methanol was allowed to evaporate overnight.
• the dried residue was dissolved in 0.5 ml PBS, pH 7.4, for biological studies.
• Isolate #615 is quite resistant in vitro to acyclovir. Three resistant plaque-purified substrains of 615 have been characterized for another purpose. Two are pure DNA polymerase mutants (615.5, 615.8) which express normal amounts of dTK and yet show in vitro and in vivo resistance to acyclovir.
• the third isolate (615.3) is a dTK deficient strain which does not phosphorylate acyclovir and phosphorylates deoxythymidine very poorly.
• the pretreatment "wildtype" isolate (sensitive to drugs as for any other HSV-1 isolate) was also plaque-purified (294.1) and used as a sensitive control.
• a laboratory-induced acyclovirresistant mutant of strain KOS, known as ACG r 4 was also used [an HSV-1 reference strain which was artificially induced to lack the dTK enzyme (viral dTK's are completely absent from this strain) through laboratory exposure to the antiviral agent, acyclovir. It lacks the dTK polypeptide, and was supplied to our lab by Dr. Don Coen, Department of Pharmacology, Harvard University].
• PRK Primary Rabbit Kidney Cells
• tissue culture grade roller tubes kept rolling at 1 rpm at 37°C.
• Tubes contained approximately 1.4 ⁇ 10 6 cells/tube.
• Each tube was infected with an moi of 10 in 1.0 ml of media and incubated for 6 hours at 37°C.
• cpm Approximately 4.8 ⁇ 10 6 counts per minute, hereinafter referred to as "cpm", of [ 125 I] -IVaraU (100 ⁇ l) were then added to each tube and incubation continued for 0.75 hours at 37°C.
• the medium was then removed from the tubes and replaced with 2.0 ml of 0.25% trypsin in EDTA, and incubated at 37°C until cells were separated from the plastic, transferred into 12 ⁇ 75 mm plastic tubes, and centrifuged to a pellet at 800 ⁇ 9 and washed 3 times in PBS, pH 7.4, 4°C, and counted in a gamma counter (Beckman).
• the "carrier-added” material was also utilized in order to determine to what extent reversal of uptake of this agent occurs, (dephosphorylation to nucleoside and loss from the infected cell).
• roller tubes were again seeded with PRK cells as described in example 4, and infected with 10 moi of the wild-type isolate, 294.1 and ACG r 4 (dTK negative) in parallel. After 6 hours of incubation at 37°C, 4 ⁇ 10 4 cpm of [ 125 I] -IVaraU were added and the incubation continued for a further 0.75 hours. The media were then removed, the monolayers washed with PBS, pH 7.4, 37°C, and the media were replaced with no nucleoside added.
• PRK cells were grown to confluence at the bottom of tissue culture grade plastic roller tubes. For this experiment, the number of cells were 1.29 ⁇ 10 6 . Inocula per cell, of 1, 0.1, 0.01, 0.001, and 0.0001 plaque-forming units, hereinafter referred to as "PFU", of HSV-1 strain 294.1 (Wild type) were used. The media were removed and replaced with Hank's "199", containing 2% inactivated fetc.1 calf serum and the various viral inocula.
• PFU plaque-forming units
• VERO cells were obtained from the American Type Culture Collection. The cells were grown to confluence and infected with HSV-1, strain F; or HSV-2, strain G, used as reference; strains. These strains were obtained from Dr. Bernard Roizman, University of Chicago (Chicago IL) .
• DUo the amount of virus required to give > 95% cytopathic effects, hereinafter referred to as "CPE” in 48 hours where no treatment is used to inhibit infection.
• CPE cytopathic effects
• Antiviral drug dilutions were made during this period, beginning at the highest concentration of IVaraU 0.065 ⁇ g/ml which was equal to a radiation dose in wells treated with [ 125 I] -IVaraU, of 0.50 ⁇ Ci/ml and then serially 2-fold diluted 16 times, and added to the wells at the end of the 1 h adsorption period in a volume of 50 ⁇ l. All experiments were performed in quadruplicate, and results are expressed as the average of those four wells at each drug dilution. The unlabeled IVaraU and the [ 125 I] -IVaraU were compared at equal concentrations and dilutions in parallel. Two types of controls are run on each 96 well plate.
• One column receives mock virus inoculation [50 ⁇ l of Medium 199 (with supplements) alone]; one other column receives mock drug treatment [50 ⁇ l of Medium 199 (with supplements) alone].
• the plates are returned to the incubator and kept at 37°C, in an atmosphere of 5% CO 2 for 2 days, followed by the dye uptake and analysis.
• Fifty ⁇ l of 15% neutral red in PBS, pH 6.0 was then added to each well, and then incubated for 45 min at 37°C, in an atmosphere of 5% CO 2 .
• the dye was then aspirated and the monolayer washed X 2 with PBS, pH 6.0.
• the medium was removed and the plate blotted to dryness. Plates were then frozen until ready for analysis.
• 100 ⁇ l of lysis buffer was added and the absorbance of each well at 570nm/410nm determined on a Dynatech® plate reader.
• Figure 6 displays in radiographic print form, a series of nuclear scans over time from an animal with HSV-1 (KOS) encephalitis infected via the cribriform plate 9 days prior to the scans. After infusion with [ 123 I] -IVaraU three scans in different head views were obtained.
• KOS HSV-1
• the agent useful as a unique radiotherapeutic tool for herpes virus infections by precise targeting of the lethal effects of alpha and/or beta radiation and/or Auger electron decay effects to the site of viral infection.
• the uses for the agent include, but are not restricted to, the following:
• the infected: uninfected cell ratio of trapping of the agent is so high, minute quantities of virus growth are detectable with this agent. Accordingly, the compound is useful as a marker of viral growth in vitro . This allows for the following:
• Deep seated infections will be detectable with this agent.
• viral diagnosis is often missed.
• the physician may not consider the diagnosis, or considers it, but is afraid of the risk of the test.
• biopsy is clinically impossible.
• in vivo diagnosis will be performed via intravenous injections of isotopes in the range of 1 to 20 mCi, total body dose. Because this requires only a very small amount of the nucleoside, the dose may be administered at one time by intravenous bolus injection. The amount of the agent in molar quantities required will be determined by the specific activity of the synthesized material. Regardless, the actual quantity of the agent in its nucleoside form administered will be less than 1 mg per day.
• ophthalmic drops or ointments or dermatological salves or ointments may be preferred with such doses as would otherwise be administered intravenously (1 to 20 mCi), applied to directly to the area of infection, followed by an assay for retained (trapped) nucleoside, sometime following natural body clearance or physical removal of the agent.
• Herpes virus-related clinical syndromes which present diagnostic problems and which might benefit from the enhanced diagnostic capabilities described herein, include, but are not limited to, the following:
• HSV and VZV infections of the eye including: retinitis, keratitis, ulceris, uveitis, retinal necrosis and zoster ophthalmicus.
• HSV meningitis often associated with genital herpes infections.
• HSV and VZV sensory nerve, root and ganglionic infections (1) HSV and VZV sensory nerve, root and ganglionic infections.
• herpes virus-induced diseases there are also a variety of herpes virus-induced diseases in the veterinary setting, each specific to a certain type of animal. Many of these viruses express the herpes virus enzyme, dTK, which specifically phosphorylates [*I] -IVaraU, and/or [*X]-XVaraU. In such situations, the veterinarian may elect to diagnose a herpes viral disease after intravenous, or intraperitoneal administration to the animal of from 0.01 to 0.50 ⁇ Ci per kg of total body weight.
• dTK herpes virus enzyme
• halogen radionuclides including 131 I, 82 Br, and others with suitable cytotoxic alpha and/or beta emission characteristics, and/or 125 I, or 77 Br, or other halogen radionuclides which display suitable Auger electron decay phenomena, localized, and thereby targeted destruction of cells actively or latently infected with HSV, VZV, or EBV will be achieved.
• Such therapy may be used in conjunction with any antiherpesviral antiviral agent, since the mechanism of antiviral action of [*I]-IVaraU, and/or [*X] -XVaraU is unique and will, therefore act synergistically with other available agents in achieving safe, but lethal radiotherapeutic antiviral effects.
• the precise form of the agent and mode of administration and dosage of this agent as an antiviral drug will be determined by the physician in ccordance with the specific clinical condition. Based on the potent in vitro antiviral effects observed, it is possible, however, to predict a dosage range of from 5 to 150 mCi total dose as the isotope, administered by intravenous injection, or 5 to 150 mCi total dose as the isotope, administered orally. Either mode of administration may be possible, depending on whether long-term administration of the agent is required.
• the amount of the agent in molar quantities required will be determined by the specific activity of the synthesized material. Regardless, the actual quantity of the agent in its nucleoside form administered will be less than 1 mg per day. In certain veterinary situations where in vivo therapy is required, either intravenous or oral or intraperitoneal therapy may be used with a total dosage range of 0.05 to 3 mCi/kg.

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