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WO1996001050A1 - Prevention et traitement d'une infection par herpesvirus humain 6 au moyen de composes d'ammonium quaternaire et/ou de ganglioplegiques - Google Patents

Prevention et traitement d'une infection par herpesvirus humain 6 au moyen de composes d'ammonium quaternaire et/ou de ganglioplegiques Download PDF

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WO1996001050A1
WO1996001050A1 PCT/US1995/008484 US9508484W WO9601050A1 WO 1996001050 A1 WO1996001050 A1 WO 1996001050A1 US 9508484 W US9508484 W US 9508484W WO 9601050 A1 WO9601050 A1 WO 9601050A1
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quaternary ammonium
ammonium compound
hhv
ion
blocking agent
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Joseph A. Baldone
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Baltech Inc
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Baltech Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines

Definitions

  • the present invention relates to a method of preventing and treating infection and related disorders caused by human herpesvirus-6 (HHV-6) . More specifically, the invention relates to administration of a quaternary ammonium compound and/or a ganglionic blocking agent before or after HHV-6 infection of the host.
  • HHV-6 herpesvirus-6
  • HHV-6 Human herpesvirus-6
  • HBLV human B- lymphotropic virus
  • HHV-6 human herpesvirus type 6
  • HHV-6 was first identified and described in 1986 by Salahuddin et al. , "Isolation of a New Virus, HBLV, in Patients with Lymphoproliferative Disorders, " Science, 234 596-601 (1986) .
  • the virus was originally isolated from human peripheral blood leukocytes from patients with associated lymphoproliferative disorders.
  • HHV-6 is distinguishable from other known members of the human herpesvirus family, such as Epstein-Barr virus (EBV) , human cytomegalovirus (CMV) , herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) , and varicella zoster virus (VZV) , serologically, morphologically, and by nucleic acid analysis.
  • EBV Epstein-Barr virus
  • CMV human cytomegalovirus
  • HSV-1 and HSV-2 herpes simplex virus type 1 and type 2
  • VZV varicella zoster virus
  • HHV-6 is distinguishable from known human and nonhuman primate herpesviruses by host range, in vi tro biological effects, and antigenic features.
  • Salahuddin et al. cited above.
  • hybridization experiments revealed the unique genome of HHV-6.
  • a 9000 base pair cloned probe of HHV-6 detected specific DNA and RNA sequences of herpesvirus infected cells, but it did not hybridize to genomic DNA of EBV, CMV, HSV-1, HSV-2, or VZV.
  • Josephs et al . cited above.
  • HHV-6 The natural host of HHV-6 is man and the primary mode of transmission is by close personal contact.
  • the latency sites of HHV-6 in the human body are salivary glands and lymphocytes.
  • HHV-6 productively infects primary CD2 T lymphocytes (CD4, CD7, and to some extent CD8) , and a minor population of B-lymphocytes in culture.
  • HHV-6 is now believed to be a cofactor in the pathogenesis of acquired immunodeficiency syndrome (AIDS) . It is most likely that HHV-6 is not exclusively an AIDS- associated agent because it has been isolated from human immunodeficiency virus (HIV) seronegative patients. It is more likely that HHV-6 plays a role in some lympho ⁇ proliferative and immune abnormalities. Salahuddin et al. , cited above.
  • HIV-1 HIV Type 1
  • Type 2 HIV-2
  • HHV-6 has been suggested as a possible cofactor because it has been identified in most patients with AIDS by virus isolation, DNA amplification techniques, and serological analysis.
  • the likelihood that HHV-6 is a cofactor of AIDS is also indicated by the fact that the virus is predominantly tropic and cytopathic in vi tro for CD4 + T lymphocytes.
  • HHV-6 may be a cofactor in some cases of AIDS by contributing to the depletion of CD4 T lymphocytes.
  • HHV-6 infection may play an important role in the progression of HIV-1 infection to AIDS by increasing HIV-1 gene expression and viral replication, consequently accelerating the cytopathic effect in co-infected CD4 + T cells.
  • HHV-6 can activate the HIV promoter. By increasing HIV promoter activity, HHV-6 may increase HIV replication, leading to an increase in cytopathic effect on coinfected human T cells. Horvat et al. , "Transactivation of the Human Immunodeficiency Virus Promoter by Human Herpesvirus 6 (HHV-6) Strains GS and Z-29 and Primary Human T-lymphocytes and Identification of Transactivating HHV-6 (GS) Gene Fragments, " J " . of Virology, 65, 2895-2902 (1991) .
  • Ganciclovir sodium is sold under the trade name Cytovene® by Syntex Laboratories, Inc.
  • foscarnet sodium is sold under the trade name Foscavir® by Astra Pharmaceutical Products, Inc. Physicians ' Desk Reference, 47th Edition, pp. 643-646 and 2397-2402 (1993) .
  • Effective alternative treatments are desirable because both GCV and FCN, which are nucleoside analogs, are highly toxic to humans and are likely to produce drug-resistant mutants, a great concern to virologists in the treatment of herpesvirus infections.
  • the present invention is directed to the use of a quaternary ammonium compound and/or a ganglionic blocking agent to treat or prevent HHV-6 infection.
  • Preferred quaternary ammonium compounds are tetraethylammonium (TEA) ion, hexamethonium ion, pentolinium ion, chlorisondamine ion, trimethidinium ion, trimethaphan ion, and homologs thereof.
  • TEA ion is employed as the quaternary ammonium compound.
  • a preferred ganglionic blocking agent is mecamylamine.
  • TEA hexamethonium ion
  • pentolinium ion pentolinium ion
  • chlorisondamine ion trimethaphan ion
  • trimethidinium ion have ganglionic blocking activity.
  • TEA chloride is, or has been in the past, commercially available from City Chemical Corp., 132 W. 22nd Street, New York, W 10011. American Druggist ' s Blue Book (1974) Am. ed.
  • the TEA ion has the following structure:
  • Disinfectant properties of quaternary ammonium compounds are also referred to in U.S. Patent No. 2,653,156, issued September 22, 1953, to Deutsch et al.
  • the topical application of quaternary ammonium compounds for the control of infections is described in U.S. Patent No. 2,886,487, issued May 12, 1959, to Kupferberg et al .
  • Ganglionic blocking drugs function to block transmission in autonomic ganglia without producing any preceding or concomitant changes in the membrane potentials of the ganglion cells.
  • Blockade of sympathetic ganglia interrupts adrenergic control of arterioles and results in vasodilatation, improved peripheral blood flow in some vascular beds, and a fall in blood pressure.
  • Ganglionic blockers do not modify the conduction of impulses in the preganglionic or postganglionic neurons, and they do not prevent the release of the neurotransmitter acetylcholine (ACh) by preganglionic impulses.
  • Ganglionic blockers occupy receptor sites on the ganglion cells, thereby stabilizing the postsynaptic membranes against the actions of ACh liberated from the presynaptic nerve endings.
  • ganglionic blocking agents Historically, the major therapeutic use of ganglionic blocking agents was in the management of hypertensive cardiovascular disease and in the production of controlled hypotension, in which a reduction in blood pressure during surgery may be sought deliberately to minimize hemorrhage in the operative field.
  • these drugs have largely been supplanted by superior agents. Pentolinium is still used to a limited extent in Europe. Goodman and Gilman 's The Pharmacological Basis of Therapeutics at 220 (1985) .
  • TEA quaternary ammonium ganglion-blocking agents used in the treatment of hypertension, peripheral vascular diseases, and other disorders of the peripheral circulation.
  • the ganglion blocking activity reversibly blocks both sympathetic and parasympathetic motor impulses.
  • TEA also lowers the blood pressure due to pronounced vasodilator action, mydriasis (pupil dilation) , cycloplegia (which may cause temporarily blurred vision) , ptosis (eyelid drooping) , and similar impairment of physical responses associated with the nerve impulse blocking action.
  • vasodilator action mydriasis (pupil dilation)
  • cycloplegia which may cause temporarily blurred vision
  • ptosis eyelid drooping
  • TEA blocks transmission of nerve impulses; it does not modify the conduction of nerve impulses. This blocking action is fully reversible and effective treatments of excessive doses are known.
  • a neurotransmitter such as acetylcholine (ACh)
  • ACh acetylcholine
  • TEA does not impair cellular metabolic processes, and changes in cell morphology due to TEA administration are reversible.
  • the Sixth Edition of Physicians ' Desk Reference to Pharmaceutical Special ties and Biologicals, J.M. Jones ed. (Medical Economics, Inc., Rutherford, NJ) reported that "EtamonTM Chloride" contained 0.1 g.
  • TEA TEA
  • HZ traumatic states
  • chest pain caused by embolism, neoplasm, pleuritis, etc. was referred to by Goodman and Gil an ' s The Pharmacological Basis of Therapeutics, Second Edition, page 633 (The MacMillan Co., New York, 1955) .
  • the mechanism of the relief of thoracic pain and HZ by TEA was unknown, but it was suggested that the mechanism was related to the observation that TEA prevented the substernal burning induced in man by lobeline, presumably caused by stimulation of pleural chemoreceptors.
  • Lobeline is a compound having the same action as nicotine, but with less potency.
  • the successful results of treating HHV-6 infection with a quaternary ammonium compound, such as TEA are surprising.
  • the antiviral agent acyclovir is effective against HSV-1, HSV-2, and varicella zoster, but is ineffective against HHV-6.
  • the antiviral agent trifluridine is effective against HSV-1, HSV-2, and vaccinia virus, but is ineffective against HHV-6.
  • Hexamethonium ion is a quaternary ammonium ganglion- blocking agent used in the treatment of hypertension, usually in combination with other hypotensive drugs, but has been largely replaced by more effective drugs. It is most often used as the chloride, bromide, or tartrate.
  • Pentolinium ion a quaternary ammonium compound with potent ganglionic blocking action of longer duration than hexamethonium, is used in the management of severe and malignant hypertension, peripheral vasospastic diseases, and to produce controlled hypotension in anesthesia. It is most often used as the tartrate.
  • Chlorisondamine ion a quaternary ammonium compound with ganglionic blocking action similar to, but more potent than, hexamethonium and pentolinium, is used in the management of severe hypertension. It is most often used as the chloride.
  • Trimethidium ion a quaternary ammonium compound that blocks ganglionic transmission at sympathetic and parasympathetic ganglia, is used in the treatment of moderate to severe hypertension. It is most often used as the methosulfate. Dorland' s Illustrated Medical Dictionary at 1397; and Stedman ' s Medical Dictionary at 1637.
  • Trimethaphan ion is a quaternary ammonium compound having short-acting ganglionic blocking activity with direct vasodilator action. It is used in surgery, particularly neurosurgery, to produce a relatively bloodless operative field (controlled hypotension) . The camsylate form is used most often. Dorland ' s Illustrated Medical Dictionary at 985; and Stedman ' s Medical Dictionary at 1160.
  • mecamylamine ion is a ganglionic-blocking agent used as a hypotensive, usually in the treatment of moderately severe hypertension.
  • the compound is similar to, but more effective than, hexamethonium, although mecamylamine is not a quaternary ammonium compound.
  • Dorland' s Illustrated Medical Dictionary at 784; and Stedman ' s Medical Dictionary at Mecamylamine HC1 is sold under the trade name Inversine® by Merck & Co. Physicians ' Desk Reference, 47th Edition (1993) .
  • the present invention overcomes the problems and disadvantages associated with current strategies for treating HHV-6 infection, such as the toxic effects of GCV and FCN, and it reduces the likelihood of creating drug-resistant mutants of HHV-6.
  • the invention provides a new therapy for the treating and preventing HHV-6 infection of animals comprising the parenteral, topical, and/or oral administration of an effective amount of a quaternary ammonium compound and/or a ganglionic blocking agent.
  • the preferred animal is a human.
  • Preferred quaternary ammonium compounds are tetraethylammonium (TEA) ion, hexamethonium ion, pentolinium ion, chlorisondamine ion, trimethidinium ion, trimethaphan ion, and homologs thereof.
  • TEA ion is employed as the quaternary ammonium compound.
  • a halide salt of a quaternary ammonium compound is employed.
  • Halide salts of TEA ion are preferred because TEA ion is readily available in deliverable form as a halide salt in single and multiple-dose forms, and because the systemic side effects of TEA halide salts in humans are known.
  • a preferred ganglionic blocking agent is mecamylamine, and homologs thereof.
  • Other preferred ganglionic blocking agents are TEA ion, hexamethonium ion, pentolinium ion, chlorisondamine ion, trimethaphan ion, mecamylamine, and homologs thereof.
  • This invention describes inhibition of HHV-6 replication and infection of cells with administration of a composition comprising a quaternary ammonium compound and/or a ganglionic blocking agent. It was completely unexpected that the administration of a quaternary ammonium compound and/or a ganglionic blocking agent would have any effect on the replication or infectivity of HHV-6. Although the compounds are known and characterized, HHV-6 was only recently discovered in 1986. The virus is morphologically and serologically distinct from known retroviruses.
  • composition can be administered orally, parenterally, or topically, or a combination of oral, parenteral, and topical administration can be used.
  • the quaternary ammonium compound can be any compound having a central nitrogen bound to four organic groups, and which is capable of treating or preventing an infection or disease in a mammal caused by HHV-6.
  • the organic groups on the central nitrogen can be alkyls, aryls, aliphatics, alicyclics, heterocyclics, aromatic cyclics, alcohols, ethers, esters, aldehydes, ketones, sulfonamides, carboxylic acids, or carbohydrates.
  • the central nitrogen may also form a ring with one or more of the organic groups.
  • the organic groups may be the same or different depending upon the particular compound.
  • the quaternary ammonium compound can be a simple monoquaternary ammonium compound, such as a tetraethyl ⁇ ammonium chloride (TEAC) ; a complex monoquaternary ammonium compound, such as phenacyl homotropinium; a bis-quaternary ammonium compound, such as pentamethonium chloride, hexamethonium chloride, and pentolinium tartrate; or an asymmetrical diquaternary ammonium compound, such as trimethidinium methasulfate and chlorisondamine chloride.
  • TEAC tetraethyl ⁇ ammonium chloride
  • a complex monoquaternary ammonium compound such as phenacyl homotropinium
  • a bis-quaternary ammonium compound such as pentamethonium chloride, hexamethonium chloride, and pentolinium tartrate
  • an asymmetrical diquaternary ammonium compound such as trimethi
  • the aliphatic groups on the central nitrogen can be alkanes, olefins, or alkynes.
  • the cyclic groups can be alicyclics, aromatics, and heterocyclics.
  • the organic groups on the central nitrogen can be alkyls having 1 to 20 carbons, hydroxalkyls, aminoalkyls, alkenyls, or substituted derivatives thereof.
  • the organic groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, allyl, or methallyl groups.
  • the alicycles and heterocyclic groups can be cyclohexyl or cyclopentyl groups, attached either directly or through side chains to the central nitrogen.
  • the organic groups on the central nitrogen can also be hydrophobic aliphatics, unsaturated aliphatics, or aliphaticaryl radicals.
  • the hydrophobic aliphatics may be long-chain alkyl, long-chain alkoxyaryl, halogen substituted long-chain alkylaryl, long-chain alkylphenoxyalkyl, or arylalkyl.
  • the organic group can also be a low molecular weight group, such as fufuryl, tertahydrofufuryl, alkyl, carbethoxyalkyl, hydroxalkyl, aminoalkyl, and alkenyl groups, or it can be a high molecular weight aliphatic hydrocarbon group, either saturated or unsaturated, and either branched or straight chain. Samples of these groups include myristyl, cetyl, stearyl, and oleyl. These groups may also contain substituents, such as hydroxyl, halogen, carbethoxy and amino.
  • the organic groups can be joined together to form a heterocyclic ring when both ends of an organic group are attached to the central nitrogen.
  • examples of such rings include pyridine, piperidine, picoline, pipicoline, pyrrol, pyrrolidine, morpholine, quinoline, quinaldine, azole, thiazole, and substituted derivatives thereof.
  • Examples of the various quaternary ammonium compounds useful in the present invention include alkyl ammonium halides, such as cetyl trimethyl ammonium bromide and dioctadecyl dimethyl ammonium chloride; alkyl aryl ammonium halides, such as octadecyl dimethyl benzyl ammonium chloride; N-alkyl-pyridinium halides, such as N-laurylpyridinium chloride; quaternary ammonium salts containing ether linkages in the molecule, such as paratertiary octylphenoxyethoxy- ethyl dimethyl benzyl ammonium chloride; quaternary ammonium compounds having oxygen in the form of amide or ester linkages, such as N- (laurylcolaminoformylmethyl) pyridinium chloride; quaternary ammonium compounds containing a sulfonamide group, such as 2-phenyl-3-p
  • the anion of the quaternary ammonium compound can be any anion that is compatible with the central nitrogen and the four organic groups of the compound.
  • the preferred quaternary ammonium compounds are TEA, hexamethonium (C6) , pentolinium, chlorisondamine, trimethidinium, and trimethaphan. As discussed above, other quaternary ammonium compounds may also be used in the present invention.
  • the preferred ganglionic blocking agent is mecamylamine, although other ganglionic blocking agents can be used, as discussed above.
  • HHV-6 infection of the animal will be prevented, or an existing infection, and conditions associated with the infection, will be alleviated.
  • the quaternary ammonium compound and/or ganglionic blocking agent is administered to the animal in a dosage effective to produce an antiviral effect against HHV-6. In another embodiment, the quaternary ammonium compound and/or ganglionic blocking agent is administered to the animal in a dosage effective to inhibit the viral function of the virus.
  • the administration of a quaternary ammonium compound and/or a ganglionic blocking agent can simultaneously achieve many of these effects.
  • the quaternary ammonium compounds and/or ganglionic blocking agents can be administered to the animal in a number of pharmaceutically acceptable methods, such as intravenously, intramuscularly, intraperitoneally, topically, orally, and/or vaginally.
  • pharmaceutically acceptable methods such as intravenously, intramuscularly, intraperitoneally, topically, orally, and/or vaginally.
  • the particular quaternary ammonium compound and/or ganglionic blocking agent selected depends on a number of factors, including the host and the method of administration.
  • the quaternary ammonium compound is administered from about 5 to about 7 mg/kg body weight by slow intravenous drip once or twice daily.
  • the quaternary ammonium compound is administered at up to about 20 mg/kg body weight intramuscularly once or twice daily.
  • the composition is administered from about 2.5 to about 5.0 mg/day/orally in two divided doses, up to about 25 mg/day/orally in three divided doses.
  • Pharmaceutically acceptable carriers for the quaternary ammonium compound and/or ganglionic blocking agent can also be employed, such as a normal sterile saline solution for systemic use or a hydrophilic ointment base for topical or vaginal administration.
  • Pharmaceutically acceptable carriers can be sterile liquids, such as water, alcohol, dimethyl- sulphoxide (DMSO) , oils, including petroleum oil, animal oil, vegetable oil, peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • Saline solutions, aqueous dextrose, and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical carriers are described in Remington 's Pharmaceutical Sciences, 18th Edi tion (A. Gennaro, ed. , Mack Pub., Easton, Pa., 1990) , incorporated by reference.
  • the concentration of the quaternary ammonium compound and/or ganglionic blocking agent is limited only by the amount that may be carried or dissolved in the carrier or diluent, but preferably is from about 1 to about 1000 mg/ml total volume, more preferably from about 50 to about 250 mg/ml. In an ointment, the concentration of the quaternary ammonium compound and/or ganglionic blocking agent can be from about 0.01% to about 99% of volume.
  • the quaternary ammonium compound and/or ganglionic blocking agent can also be encapsulated or placed in pill form for oral administration to the host. The dosages of the quaternary ammonium compound and/or ganglionic blocking agent can be readily determined by the skilled artisan.
  • the quaternary ammonium compound has ganglionic blocking activity.
  • Preferred quaternary ammonium compounds having ganglionic blocking activity include TEA ion, hexamethonium ion, pentolinium ion, chlorisondamine ion, trimethidinium ion, trimethaphan ion, and homologs thereof.
  • An appropriate anion, such as chloride or bromide, is present with the ganglionic blocking agent in pharmaceutical preparation.
  • the objective of this experiment was to evaluate the potential toxicity of TEAC on Molt-3 cells.
  • the HHV-6 strain used was Z-29, deposited with the A.T.C.C., and the cell type was Molt-3, also deposited with the A.T.C.C.
  • TEAC TEAC was dissolved in water (100-200 mg/ml) and filter sterilized.
  • Stock drug solution was serially diluted in RPMI media with 10% fetal bovine serum to obtain the desired final drug concentrations.
  • the pH of the drug-containing media was between 7.9 and 8.0.
  • Molt-3 cells were incubated in six well Costar dishes
  • Drug concentrations of 1 mg/ml to 40 mg/ml were toxic to Molt-3 cells at day 3. Drug concentrations of 0.5 mg/ml or lower had no retarding effect on the growth of Molt-3 cells. A concentration of 0.5 mg/ml of TEAC was selected to maintain uninfected and HHV-6 infected Molt-3 cells.
  • the objectives of this experiment were to determine the effect of TEAC on the replication of HHV-6 in vitro.
  • Example 2 The same materials used in Example 1 were used in Example 2.
  • Molt-3 cells at 3 x 10 cells/well were incubated (in duplicate) with 0.4 ml of untreated virus (2 x 10 PFU/0.4 ml) for 3 hours.
  • the cultures were rehydrated with 4 ml of growth media containing the appropriate drug concentration, and incubated at 37° in a humidified C0 2 incubator.
  • the results are shown in Table 2. The percentages reported are an average of duplicate values.
  • TEAC did not have any effect on the replication of HHV-6.
  • Drug concentrations of 1 to 2 mg/ml showed a 50% reduction in the replication of HHV-6 at day 3.
  • the objective of this experiment was to determine the effect of TEAC on the infectivity of HHV-6 in vi tro.
  • Example 3 The same materials used in Example 1 were used in Example 3.
  • HHV-6 1.2 ml of HHV-6 (2 x 10 5 PFU/0.4 ml) was incubated with the appropriate drug concentration at 37°C overnight.
  • the virus was collected by centrifugation, washed with PBS IX, and re-suspended in 1.2 ml of RPMI media containing 10% fetal bovine serum.
  • An aliquot of drug treated virus (0.4 ml) was mixed with Molt-3 cells at 3 x 10 cells/well (in duplicate) and incubated for 3 hours.
  • the cultures were rehydrated with 4 ml of growth media containing 0.5 mg/ml TEAC. Incubation was continued at 37°C in a humidified C0 2 incubator.
  • the objective of this experiment was to determine the effective concentrations of TEAC required to reduce 50-90% of HHV-6 replication or infectivity in vi tro ("IC50" and "IC90") .
  • Example 2 The same materials used in Example 1 were used in Example .
  • HHV-6 was incubated in wells with appropriate drug concentrations of TEAC overnight at 37°C. The virus was washed off the wells and re-suspended in drug-free media. Drug-treated and untreated (0 mg/ml TEAC) HHV-6 were adsorped to Molt-3 cells in the presence of 0.5 mg/ml TEAC for four hours at 37°C (in duplicate) . The treated virus was then rehydrated with growth media containing 0.5 mg/ml TEAC and incubated at 37°C. The untreated control virus was adsorped and rehydrated in drug-free media.
  • CPE cytopathic effect
  • TEAC At 0.5 mg/ml to 9 mg/ml, TEAC showed no antiviral efficacy during HHV-6 infection in vitro. However, 10 mg/ml of TEAC showed 40% virucidal activity.
  • the estimated IC50 and IC90 for TEAC are 10 mg/ml and 20 mg/ml, respectively.
  • the objective of this experiment was to determine whether treatment of cells with TEAC prior to HHV-6 infection enhances the virucidal or antiviral efficacy of the drug (the effect on viral receptors on the cell surface) .
  • Example 5 The same materials used in Example 1 were used in Example 5.
  • Molt-3 cells were incubated in wells in the presence of 0.5 mg/ml TEAC or GCV (28.5 ⁇ M) .
  • a control group of Molt- 3 cells was incubated in drug-free media.
  • HHV-6 was incubated separately with 0 mg/ml as a control, 0.5 mg/ml, 10 mg/ml, and 20 mg/ml of drug.
  • Drug-treated and untreated cells were infected with drug- treated and untreated virus in parallel. The cells were then adsorped at 37°C for 4 hours, followed by rehydration in media containing 0.5 mg/ml TEAC at 37°C. At day 18, aliquots were plated and stained as in Example 4.
  • Example 4 The results of Examples 4 and 5 indicate that under these experimental conditions, the antiviral efficacy of TEAC does not differ significantly from that of the more toxic GCV. Moreover, the use of TEAC is preferable over the use of GCV to treat HHV-6 infections because unlike GCV, TEAC is a non- nucleoside analog. TEAC may therefore be less likely to produce drug resistant mutants. The data also suggests that TEAC disrupts cell receptors as well as interferes with viral replication. Example 6
  • the objective of this experiment was to evaluate the potential toxicity of mecamylamine on Molt-3 cells.
  • Example 6 The same materials used in Example 1 were used in Example 6.
  • mecamylamine was dissolved in water (2 mg/ml) and filter sterilized.
  • the stock drug solution was serially diluted in RPMI media with 10% fetal bovine serum to obtain the desired final drug concentrations.
  • the pH of the drug media was between 7.9 and 8.0.
  • the objective of this experiment was to determine the effect of mecamylamine on the replication of HHV-6 in vi tro .
  • Example 1 The same materials used in Example 1 were used in Example 1.
  • CPE cytopathic effect
  • the objective of this experiment was to determine the effect of mecamylamine on the infectivity of HHV-6 in vi tro.
  • Example 8 The same materials used in Example 1 were used in Example 8.
  • HHV-6 (1.2 ml at 2 x 10 5 PFU/0.4 ml) was incubated with the appropriate drug concentration at 37°C overnight. The virus was collected by centrifugation, washed with PBS IX, and re-suspended in 1.2 ml of RPMI media containing 10% fetal bovine serum. An aliquot of drug treated virus (0.4 ml) was
  • Molt-3 cells 3 x 10 cells/well, in duplicate
  • the cultures were rehydrated with 4 ml of drug-free growth media. Incubation was continued at 37°C in a humidified C0 2 incubator.
  • the percent infected cells was determined as in Example 7. Mecamylamine had no effect on the infectivity of HHV-6 at 30-120 ⁇ g/ml.
  • Examples 6-8 indicate that mecamylamine prevents the entry of HHV-6 into cells, most likely by disrupting cell receptors for the virus.

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Abstract

L'invention se rapporte à un procédé amélioré de traitement ou de prévention de maladies causées par ou associées à l'infection par herpèsvirus humain 6 (HHV 6), et consistant à administrer une dose thérapeutique efficace d'un composé d'ammonium quaternaire et/ou d'un ganglioplégique.
PCT/US1995/008484 1994-07-05 1995-07-05 Prevention et traitement d'une infection par herpesvirus humain 6 au moyen de composes d'ammonium quaternaire et/ou de ganglioplegiques Ceased WO1996001050A1 (fr)

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Cited By (3)

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US5986142A (en) * 1997-09-23 1999-11-16 Poli Industria Chimica Spa Process for preparing bicycloheptanamine compounds
EP1868594A4 (fr) * 2005-03-24 2009-11-11 Dow Pharmaceutical Sciences Ganglioplegiques pour traiter des maladies epitheliales
WO2015048098A1 (fr) * 2013-09-24 2015-04-02 Washington University Procédé de diagnostic pour une maladie infectieuse utilisant l'expression de gène endogène

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5986142A (en) * 1997-09-23 1999-11-16 Poli Industria Chimica Spa Process for preparing bicycloheptanamine compounds
EP1868594A4 (fr) * 2005-03-24 2009-11-11 Dow Pharmaceutical Sciences Ganglioplegiques pour traiter des maladies epitheliales
WO2015048098A1 (fr) * 2013-09-24 2015-04-02 Washington University Procédé de diagnostic pour une maladie infectieuse utilisant l'expression de gène endogène
US11286529B2 (en) 2013-09-24 2022-03-29 Washington University Diagnostic methods for infectious disease using endogenous gene expression

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