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WO1992003137A1 - Traitement des demences, des myelopathies, des neuropathies peripheriques et des pertes de vision liees au sida - Google Patents

Traitement des demences, des myelopathies, des neuropathies peripheriques et des pertes de vision liees au sida Download PDF

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WO1992003137A1
WO1992003137A1 PCT/US1991/006048 US9106048W WO9203137A1 WO 1992003137 A1 WO1992003137 A1 WO 1992003137A1 US 9106048 W US9106048 W US 9106048W WO 9203137 A1 WO9203137 A1 WO 9203137A1
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gpl20
patient
neurons
compound
levemopamil
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PCT/US1991/006048
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Stuart A. Lipton
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The Children's Medical Center Corporation
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates.to the treatment of nervous system disorders caused by infection with human immunodeficiency virus (HIV) .
  • HAV human immunodeficiency virus
  • HIV infection in humans causes general immunosuppression and involves other disorders, such as myelopathy, vision loss, peripheral neuropathy, and other neurological manifestations including a dementing neurological disorder, i.e., the AIDS dementia complex, the latter of which is a common and important cause of morbidity in HIV-infected patients. HIV infection has been documented in various areas of the CNS, including the cerebral cortex, spinal cord, and retina. Price et al. (1988, Science 239:586) and Ho et al.
  • the invention features a method of reducing damage to neurons in a human patient infected with a human immunodeficiency virus, by administering to the patient levemopamil, or a physiologically-acceptable salt thereof, in a concentration effective to cause a reduction in the gpl20-responsive rise in intracellular free Ca ++ ion concentration in, and subsequent death of, the neurons of that patient.
  • human immunodeficiency virus is meant all types and variants of human immunodeficiency virus (HIV) including HIV-1, HIV-2, LAV, and others.
  • the neurons may derive from the central or peripheral nervous system.
  • the blood of the infected patient contains antibodies to HIV; most preferably, the patient manifests symptoms of AIDS related complex or of acquired immune deficiency syndrome.
  • the levemopamil most preferably is administered orally or intravenously.
  • the method may also include administration to the patient of a second compound that is capable of reducing the gpl20-responsive rise in intracellular free Ca ++ ion concentration, in a concentration effective to cause such reduction.
  • Most preferred second compounds are the calcium channel antagonists listed in Tables 1, 2, and 3, including nifedipine, verapamil, nitrendipine, diltiazem, Smith Kline drug no.
  • NMDA N- methyl-D-aspartate
  • Other preferred second compounds include antagonists of the N- methyl-D-aspartate (NMDA) receptor-channel complex, including channel blockers, receptor antagonists, or agents acting at either the glycine co-agonist site or any of several modulation sites such as the Zinc site, the Magnesium site, the polyamine site, the pH-sensitive site, or the redox modulatory site.
  • NMDA receptor-channel antagonists are those listed in Table 4, for example, MK-801 and D-2-amino-5- phosphonovalerate (APV) .
  • the invention is useful for the reduction or prevention (including prophylactic treatment) of dementia, myelopathy, peripheral neuropathy, vision loss or other neurological manifestations associated with infection by a human immunodeficiency virus.
  • Brain uptake index (BUI) analysis indicates that levemopamil passes readily from the blood to the brain, facilitating a therapy which is both extremely rapid and unusually potent.
  • Fig. 1 is a dose-response curve showing retinal ganglion cell death at different gpl20 concentrations
  • Fig. 2 is a graph of retinal cell survival in the presence of recombinant gpl20 and antiserum
  • Fig. 3(a) is a graph of kinetics of intracellular free Ca 2+ concentration ([Ca 2+ ]i) in a retinal ganglion cell in response to various doses of gpl20, and (b) is a steady state dose-response graph of gpl20 concentration versus [Ca 2+ ]i;
  • Fig. 4 is a bar graph of gpl20-promoted rise in [Ca 2+ ]i in the presence of gpl20 alone or gpl20 that has been immunoprecipitated with gpl20 antiserum.
  • the drug levemopamil also known as (S)-emopamil;
  • U.S. Patent No. 4,596,820 is a calcium channel blocker which readily passes through the blood-brain barrier (i.e., is CNS permeable). This drug may be used to treat central nervous system disorders, such as myelopathy, vision loss, and dementia, associated with HIV-I infection.
  • Levemopamil may be administered by any one of a number of routes.
  • administration may be oral or intravenous, at a suggested divided dosage of 0.1 to 50 mg/kg body weight, two or three times daily. Less preferably, administration may be intrathecally or intravitreally, at a suggested dosage of 0.1 to 50 mg/kg body weight, two or three times daily.
  • a second Ca++ channel antagonist may be administered to a patient in conjunction with levemopamil. Dosage of preferred second compounds is as follows. Nimodipine or Smith Kline drug no.
  • 9512, nicardipine, flunarizine, or diproteverine may be administered orally or intravenously, at a suggested divided dosage of 60 to 1200 mg/day.
  • MK-801 may be used at a daily dose of 0.01 to 5.0 mg/kg.
  • Nifedipine is administered at a dosage of 20 to 800 mg/day; verapamil at a dosage of 80 to 720 mg/day; and diltiazem at a dosage of 60 to 960 mg/day.
  • Each of these compounds is preferably administered intrathecally or intravitreally.
  • the effective dose of other suggested second compounds (e.g., those in Tables 1-4) will range from 0.01 to 1000 mg/kg.
  • V-I infection is detrimental to cells associated with the nervous system; such nerve cell damage is the result of a gpl20 protein-mediated increase in intracellular Ca ++ .
  • the detailed description also outlines assays which provide one skilled in the art with the necessary guidance to determine levemopamil's maximum efficacy level.
  • In Vitro Neuronal Cell Death Assay Neuronal cell death may be assayed by incubating retinal ganglion cells in vitro with purified native or recombinant gpl20 and scoring live cells. The ability of the levemopamil to reduce neuronal cell death is determined by scoring live cells which have been incubated overnight with both gpl20 and the drug.
  • Retinal ganglion cells from postnatal rats are identified and their viability ascertained as follows. Under general anesthesia, the fluorescent dye granular blue (Mackromolekulare Chemic, Umstadt, FRG) is injected as approximately a 2% (w/v) suspension in saline into the superior colliculus of 4- to 7-day-old Long Evans rats (Charles River Laboratory, Wilmington, MA) . Two to 7 days later, the animals are killed by decapitation and enucleated, and the retinas quickly removed.
  • the fluorescent dye granular blue Mackromolekulare Chemic, Umstadt, FRG
  • the retinas are then dissociated and cultured in Eagle's minimum essential medium (MEM, catalog #1090, Gi .no Grand Island, NY), supplemented with 0.7% (w/v) methylcellulose, 2 mM glutamine, 1 ⁇ g/ml gentamicin, 16mM dextrose, and 5%(v/v) rat serum, as described in Lipton et al., J. Physiol. 385:361. 1987.
  • the cells are plated onto 75 mm 2 glass coverslips coated with poly-L-lysine in 35 mm tissue culture disL.es; gpl20 is then added. Sibling cultures receive various doses of levemopamil, with and without gpl20.
  • the cell-culture medium is exchanged for physiological saline containing 0.0005% fluorescein diacetate for 15-45 s, and then cells are rinsed in saline.
  • Retinal ganglion cells that do not contain the fluorescein dye (and thus were not living) often remain visible under both phase-contrast and UV fluorescence optics, the latter because of the continued presence of the marker dye granular blue; other dead retinal ganglion cells disintegrate and only debris remains.
  • the viable retinal ganglion cells display not only a blue color in the UV light but also a yellow-green fluorescence with filters appropriate for fluorescein.
  • Gpl20 is produced and purified as follows.
  • Two native isolates of gpl20, RF2 and 3B, (Brenneman et al., 1988, supra; Nature 335:445; National Cancer Institute, Frederick, MD) are purified by immunoaffinity chromatography, as described by Robey et al. (1986, Proc. Nat. Acad. Sci. USA 83:7023). Pyle et al. (1988, AIDS Re ⁇ Hum. Retrovir. 3_:387), and Kornfeld et al. (1988, Nature 335:4-5)
  • reco binant gpl20 derived from the gene encoding gpl20-3B is obtained as follows.
  • Recombinant gpl20 is produced by transfection of a Chinese Hamster Ovary (CHO). cell line (ATCC) with a plasmid containing isolate 3B envelope coding sequences encoding amino acids 61-531 (Lasky et al., 1986, Science 233:209) .
  • the gene is truncated to remove the native amino-terminal signal sequence and the carboxy-terminal transmembrane domain, and then ligated in-frame to the herpes simplex virus glycoprotein-D signal sequence (Ber an et al., 1985, Science 227:1490) to allow the envelope protein to be constitutively secreted by the CHO cell line. Production in a mammalian cell ensures that the envelope protein is glycosylated.
  • This envelope glycoprotein, rgpl20-3B is purified by immunoaffinity chromatography to 5 parts in a million (99.995%) pure based on estimates from polyacrylamide gel electrophoresis and Western blotting.
  • the preparations of gpl20 (at low concentrations) are highly labile in that they have to be freshly thawed (with refreezing avoided) in order to display activity.
  • qpl20 Increases Neuronal Cell Death In Vitro
  • Neuronal cell death is assayed by incubating retinal ganglion cells in vitro with purified native or recombinant gpl20 and scoring live cells.
  • Fig. 1 is a dose-response curve for concentrations of gpl20 ranging from 10 "9 M to less than 10 ⁇ 13 M, and shows that incubation of native purified gpl20 (RF2) or recombinant gpl20 preparations with cultured retinal cells resulted in the death of a significant number of ganglion cells within 24 h. A significant increase (P ⁇ 0.01) in cell death was observed at gpl20 concentrations above 2 x 10 ⁇ 12 M. Living cells were scored without knowledge of treatment in each culture. Control cultures had counts ranging from 95 to 250 retinal ganglion cells per 75 mm coverslip, which corresponded to approximately 1% of the total retinal cell population.
  • Goat anti-gpl20 immune sera is prepared by primary and secondary intramuscular immunizations of recombinant fragments of the 3B isolate of gpl20 plus Freund's adjuvant. Prior to these injections, preimmune serum is collected from each goat. The presence of gpl20 antibodies in the postimmune serum is verified by polyacrylamide gel electrophoresis of immunopurified gpl20 and Western blotting.
  • Fig. 2 shows that anti-gpl20 antisera prevented neuronal cell killing of rat retinal ganglion cells by recombinant envelope protein (rgpl20-3B) .
  • Retinal cultures from 8 day-old rats were plated in the presence or absence of 20 pM gpl20 plus either postimmune serum containing polyclonal gpl20 antibodies from goat G1084, or preimmune serum from the same goat.
  • Sera were used at a concentration of 1:500 diluted in control growth medium.
  • Fig. 2 represents data from 5 separate assays; error bars represent standard error of the mean.
  • Statistical analysis was performed as described above.
  • the concentration of intracellular free Ca ([Ca 2+ ]i) is measured in postnatal rat retinal ganglion cells and hippocampal neurons by digital imaging microscopy with the Ca 2+ sensitive fluorescent dye fura 2, as follows. Retinal ganglion cells are cultured from 1-to 2-week-old Long Evans rats as described (Leifer, et al. , Science 224: 303, 1984; Lipton et al., J. Physiol. 385:361. 1987).
  • the ganglion cells are identified by the presence of retrogradely transported red fluorescent dyes (Dil or rhodamine-labeled microspheres) or by morphological and immunofluorescence criteria (e.g., the large or ⁇ -like ganglion cells which stain with neurofilament antibodies; Drager et al., Nature 309:624,. 1984) .
  • red fluorescent dyes Di or rhodamine-labeled microspheres
  • morphological and immunofluorescence criteria e.g., the large or ⁇ -like ganglion cells which stain with neurofilament antibodies; Drager et al., Nature 309:624,. 1984.
  • the fluid bathing the neurons consists of Hanks' balanced salts: 136.7 M NaCl, 1 mM NaHC0 3 , 0.34 mM Na 2 HP0 4 , 0.44mM KH 2 P0 4 , 5.36 mM KC1, 2.5 mM CaCl 2 , 0.5 mM MgS0 4 , 0.5 mM MgCl 2 , 5 mM Hepes NaOH, 22.2 mM glucose, and phenol red indicator (0.001% v/v) ; pH 7.2.
  • Coat protein gpl20 and other substances are usually applied to the neurons by pressure ejection after dilution in this bath solution.
  • High K + solutions are prepared by substituting KC1 for NaCl.
  • Neuronal [Ca 2+ ]i is analyzed with fura 2-acetoxy-methyl ester (AM) as described [Grynkiewicz, et al., J. Biol. Chem. 260:3440 (1985); Williams et al., Nature 318:558 (1985); Connor et al., J. Neurosci. :1384 (1987); Connor et al. , Science 240:649 (1988); Cohan et al., J. Neurosci. 7:3588 (1987); Mattson, et al., ibid, :3728 (1989)].
  • AM fura 2-acetoxy-methyl ester
  • the cultures After adding Eagle's minimum essential medium containing 10 ⁇ M fura 2-AM to retinal or hippocampal cell neurons, the cultures are incubated at 37°C in a 5% C0 2 /95% air humidified chamber and then rinsed. The dye is loaded, trapped, and deesterified within 1 hour, as determined by stable fluorescence ratios and the effect of the Ca ionophore ionomycin on [Ca 2+ ]i is measured. During Ca 2+ imaging, the cells are incubated in a solution of Hepes-buffered saline with Hanks' balanced salts.
  • the [Ca 2+ ]i is calculated from ratio images that are obtained by measuring the fluorescence at 500 n that is excited by 350 and 380 nm With a DAGE MTI 66 SIT or QUANTEX QX-100 Intensified CCD camera mounted on a Zeiss Axiovert 35 microscope. Exposure time for each picture is 500 ms. Analysis is performed with a Quantex (Sunnyvale, CA) QX7-210 image-processing system. Since cells are exposed to ultraviolet light only during data collection (generally less than a total of 20 s per cell) , bleaching of fura 2 is minimal. qpl20 Affects the Intracellular Concentrati •on of Ca2+
  • the effects of levemopamil on gp120-mediated neuronal cell death and its ability to antagonize calcium channels may be tested as follows. Cultures of retinal ganglion cells receive gpl20 (20 pM) and/or levemopamil (10 ⁇ M) at the time of plating (as described above) , and neuronal cell survival is assayed one day later (also as described above) . Each experiment is reproduced in 4 replicate tissue culture dishes and a mean value calculated. Survival of clustered retinal ganglion cells in the control group (i.e., those treated with gpl20 only) is compared to those treated with gpl20 plus levemopamil. Preferably this experiment is repeated a number of times.
  • Too little [Ca 2+ ]i may inhibit survival while too much [Ca 2+ ]i may also lead to cell death. In between these two extremes, survival may be enhanced.
  • the drug alone may be toxic to neurons for some other, unrelated, reason although in that case it would be difficult to explain the finding that survival in the case of nifedipine was slightly better with the combination of gpl20 plus nifedipine compared to nifedipine alone.
  • the effect of using lower doses of levemopamil on neuronal survival following gpl20 treatment may be tested as follows. Treated cultures receive gpl20-3B (20 pM) and/or levemopamil at a range of concentrations (e.g., between 10 nM and 1 ⁇ M) at the time of plating, and retinal ganglion cell survival is assayed one day later. By fine tuning the dose-response curve, it is possible to find an optimal level of levemopamil that produces minimal death on its own and yet substantially blocks the toxicity mediated by gpl20. Evidence from equivalent experiments involving other calcium channel antagonists, such as nifedipine and nimodipine, indicate an optimal drug concentration of 0.1 ⁇ M; this concentration is suggested as an optimal levemopamil concentration as well.
  • nifedipine and nimodipine calcium channel antagonists
  • retinal ganglion cells are loaded with fura 2, as described above.
  • the viral envelope protein * pl20 200 pM is then applied by puffer pipette to neurons previously bathed in normal medium or in medium containing levemopamil (e.g., 100 nM to 10 ⁇ M) for several min.
  • Intracellular Ca concentration is measured as described above.
  • gpl20 produces an increase in [Ca ]i (see above) .
  • levemopamil efficacy would be evidenced by a partial or total block of such an increase in the intracellular Ca concentration; however, the best measure of efficacy is prevention of neuronal cell injury in the face of HIV-related insult.
  • Levemopamil's Effect on Current Flow Through Calcium Channels in the Presence of qpl20 The following assay of neuronal cell function tests the effect of a calcium channel antagonist such as levemopamil on Ca 2+ ion flow through Ca 2+ channels. Without being bound to any theory as to the mechanism whereby gpl20 increases cell death, it is possible that gpl20 increases current flow across Ca channels.
  • Ca 2+ currents are measured in the presence of gpl20 in retinal ganglion cells in the presence or absence of levemopamil (e.g., 100 nM - 10 ⁇ M) .
  • levemopamil e.g. 100 nM - 10 ⁇ M
  • current carried by Ba through calcium channels is measured during the application of 20 pM gpl20-RF2 with or without levemopamil (e.g., 100 nM - 10 ⁇ M) . All traces are obtained in the presence of gpl20.
  • the Ca + current in hippocampal neurons has been shown to be partially suppressed by verapamil (100 ⁇ M) (Yaari et al., 1987, Science 235:680) ; in addition, novel calcium channel blockers or G proteins and intracellular messengers that affect their efficacy, may prove useful in this regard (Olivera et al., 1985, Science 230:338, Dolphin et al., 1987 J. Phvsiol. 386:1: and Yaari et al., 1987, Science 238:1288) . Miller (supra) showed that hippocampal neurons were more sensitive to calcium channel antagonists than were striatal neurons. This vTMiability can probably be attributed to the fact that c _y a prolonged component of Ca + current (similar to L-type current) is sensitive to dihydropyridines and probably levemopamil.
  • a second compound capable of either antagonizing Ca 2+ channels or antagonizing NMDA-receptor channels (or their effects) may be administered to a patient in conjunction with levemopamil.
  • Preferred calcium channel antagonists are listed in Tables l, 2 and 3. TABLE 1
  • Antagonists of the Voltage Dependent Calcium Channel include dihydropyridines (e.g., nimodipine) phenylalkylamines (e.g., verapamil, D-600, D-888) benzothiazepines (e.g., diltiazem and others) bepridil and related drugs diphenylbutylpiperdines diphenylpiperazines (e.g., flunarizine/cinnarizine series)
  • dihydropyridines e.g., nimodipine
  • phenylalkylamines e.g., verapamil, D-600, D-888
  • benzothiazepines e.g., diltiazem and others
  • bepridil and related drugs diphenylbutylpiperdines diphenylpiperazines (e.g., flunarizine/cinnarizine series)
  • HOE 166 and related drugs fluspirilene and related drugs toxins and natural compounds (e.g., snail toxins - ⁇ conotoxin GVIA and GVIIA, maitotoxin, taicatoxin, tetrandine, hololena toxin, plectreurys toxin, funnel-web spider venom and its toxin fraction
  • toxins and natural compounds e.g., snail toxins - ⁇ conotoxin GVIA and GVIIA, maitotoxin, taicatoxin, tetrandine, hololena toxin, plectreurys toxin, funnel-web spider venom and its toxin fraction
  • Preferred second compounds include the following drugs, of which the most preferred are those that are capable of crossing the blood-brain barrier, for example, nimodipine (Miles Pharmaceuticals, West Haven, CT) , Smith Kline drug no. 9512 (Smith Kline, French-Beecham, Philadelphia, PA) , diproteverine (Smith, Kline, French-Beecham) , and flunarizine. Less preferred antagonists are those that are less CNS permeable, for example, verapamil (Calan, G.D.
  • Ca 2+ channel antagonists which may be useful are mioflazine, flunarizine, bepridil, lidoflazine, CERM-196, R-58735, R-56865, Ranolazine, Nisoldipine, Nicardipine, PN200-110, Felodipine, Amlodipine, R-(-)-202-791, and R-(+)-Bay-K-8644 (Miles, Bayer), whose chemical formulae are described in Boddeke et al., Trends in Pharmacologic Sciences, 1989, .10:397 (hereby incorporated by reference) and Triggle et al. , Trends in Pharmacologic Sciences (1989) 10:370.
  • any second calcium channel antagonist compound e.g., those described above
  • effectiveness in preventing neurological disorders associated with HIV-1 (or other HIV) infection is determined by screening the drug using one or more of the following assays of neuronal cell function: neuronal cell death, detection of intracellular free Ca ion concentration in neurons, and detection of current flow through Ca 2+ channels (see above) .
  • Any suitable antagonist of the N-methyl-D- aspartate (NMDA) subtype of glutamate receptor-channel complex may also be used as a second compound in conjunction with levemopamil.
  • Preferred antagonists are listed in Table 4.
  • the antagonist can be a channel blocker, a receptor antagonist, or act at the glycine co- agonist site or at any of several modulation sites such as the Zinc site, the Magnesium site, the polyamine site, the pH sensitive site, or the redox modulatory site (see, e.g., Table 4).
  • Many antagonists of the NMDA receptor have been identified (Watkins et al. , Trends in Pharmacological Sci. 11:25, 1990, hereby incorporated by reference) .
  • modulatory substances include those known to cause oxidation of the redox site of the NMDA receptor (U.S.S.N. 391,778, filed August 9, 1989, and incorporated herein by reference) , and oxidized or reduced glutathione.
  • Dextrorphan, dextromethorphan and derivatives or morphinans (noncompetitive NMDA receptor antagonist) (Hoffman La-Roche)
  • Phencyclidine (PCP) and derivatives and pyrazine compounds are examples of Phencyclidine (PCP) and derivatives and pyrazine compounds.
  • MDL 27,266 (Merrell Dow) and triazole-one derivatives.
  • Monosialogangliosides e.g., GM1 of Fidia Corp.
  • CGS-19755 and other piperidine derivatives CIBA-GEIGY
  • D-2-amino-5-phosphonovalerate NMDA recertor antagonist
  • D-2-amino-7-phosphonoheptanoate AP7, selective NMDA receptor antagonist
  • CPP [3-(2-Caroxypiperazin-4-y)propyl-l-phosphonic acid], a selective NMDA receptor antagonist that is a rigid analog of AP7.
  • Indole-2-carboxylic acid (competitive antagonist of potentiation at glycine co-agonist site of NMDA receptor) .
  • DNQX (6,7-dichloroquinoxaline-2-3-dione and other
  • DNQX is a specific glycine co-agonist site antagonist of the NMDA receptor
  • Ketamine non-competitive open channel blocker of NMDA receptor-operated channels
  • O-phosphohomoserine an NMDA antagonist
  • Tiletamine and other cyclohexane derivatives non ⁇ competitive NMDA antagonists
  • Arcaine or related biguanidines and biogenic polyamines antagonist of the polyamine modulatory site
  • Diethylenetriamine antagonist of the polyamine site
  • 1,10-Diaminodecane inverse agonist of the polyamine site
  • 21-aminosteroid such as U74500A, U75412E and U74006F (Upjohn) (interfere with events linking the NMDA receptor to overstimulation by calcium)
  • an antagonist may be tested for utility in the method of the invention using various types of neuronal cells from the central nervous system and the assays described herein, as long as the cell can be isolated intact using conventional techniques.
  • Retinal cultures were used in the assays described herein (but hippocampal cortex neurons have also been used, e.g., in assays of neuronal death and intracellular calcium) , because retinal cells can be produced from postnatal mammals, are well-characterized, and contain a central neuron, the retinal ganglion cell, that can be unequivocally identified with fluorescent labels.
  • a substantial portion of retinal ganglion cells in culture display both functional synaptic activity and bear many, if not all, of the neurotransmitter receptors found in the intact retina and brain.
  • An effective antagonist will cause a decrease in HIV-1-associated neuronal cell damage or death, and will prevent the rise in intracellular Ca 2+ ion concentration that occurs in the presence of gpl20.
  • an effective antagonist will decrease Ca ++ ion influx through neuronal calcium channels to a degree sufficient to reduce neuronal cell death, while not completely blocking Ca ++ ion influx, an event which itself might kill neuronal cells.
  • the antagonist may be compounded into a pharmaceutical preparation, using pharmaceutical compounds well-known in the art; the exact formulation of the antagonist compound depends upon the route of administration. Other Embodiments Other embodiments are within the following claims.
  • the method of the invention may be used for treatment of dementia, myelopathy, peripheral neuropathy, or vision loss associated with infection by a human immunodeficiency virus.
  • the method can be used whether or not the patient manifests symptoms of the AIDS related complex or AIDS itself, and thus the method of the invention may be used as a prophylactic treatment for damage to CNS neurons, after HIV infection.
  • levemopamil may be administered by any means that allows the compound access to the central nervous system.
  • levemopamil is administered orally or intravenously; alternatively, it may be administered intrathecally to the brain and/or spinal cord, or intravitreally to the retina.
  • the method of the invention also includes administering to a single patient levemopamil and one or more of the useful compounds from multiple categories of modulators of intracellular Ca + concentration (e.g., those listed in Tables 1-4) .

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Abstract

Le procédé décrit, qui sert à réduire les lésions causées aux neurones chez un patient infecté par le virus de l'immunodéficience humaine, consiste à administrer au patient du levemopamil, ou un sel physiologiquement tolérable de ce dernier, selon une concentration suffisante pour faire baisser l'augmentation, en réponse au gp120, de la concentration d'ions Ca++ libres dans les neurones du patient et pour en réduire les lésions qui s'en suivraient.
PCT/US1991/006048 1990-08-23 1991-08-23 Traitement des demences, des myelopathies, des neuropathies peripheriques et des pertes de vision liees au sida WO1992003137A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
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WO1994014441A1 (fr) * 1992-12-22 1994-07-07 Aktiebolaget Astra Utilisation d'une dihydropyridine enantiomere
WO1994027602A1 (fr) * 1993-06-01 1994-12-08 Cortex Pharmaceuticals, Inc. Utilisation d'agonistes des recepteurs metabotropiques pour le traitement de neurodegenerescences evolutives
WO1994025029A3 (fr) * 1993-04-26 1994-12-22 Janssen Pharmaceutica Nv Utilisation de sabeluzole dans le traitement de maladies neurodegeneratives chroniques
EP0664127A2 (fr) * 1993-12-28 1995-07-26 Nippon Zoki Pharmaceutical Co., Ltd. Composition pharmaceutiques contenant des dérivés de l'isoquinoline
EP0698391A1 (fr) * 1994-07-29 1996-02-28 Synthelabo Utilisation de l'ifenprodil et de ses diastéréoisomères pour la préparation de médicaments utiles dans le traitement des neuropathies périphériques et des maladies neurodégénératives centrales
WO1997033582A1 (fr) * 1996-03-14 1997-09-18 Synthelabo Compositions d'antagonistes de site polyamine
WO2002062795A3 (fr) * 2001-02-02 2003-05-30 Mitsubishi Pharma Corp Composes de dihydropyrazolopyridine et leur utilisation pharmaceutique
US6977262B2 (en) 2001-02-02 2005-12-20 Mitsubishi Pharma Corporation Dihydropyrazolopyridine compounds and pharmaceutical use thereof
US7732467B2 (en) 2003-05-15 2010-06-08 Alzheimer's Institute Of America, Inc. Method for reducing amyloid deposition, amyloid neurotoxicity and microgliosis
US8236347B2 (en) 2007-10-05 2012-08-07 Alzheimer's Institute Of America, Inc. Pharmaceutical compositions for reducing amyloid deposition, amyloid neurotoxicity, and microgliosis
US20130053411A1 (en) * 2010-05-03 2013-02-28 Tsh Biopharm Corporation Ltd. Pharmaceutical composition and method for treating hypertension
US8901171B2 (en) 2010-01-27 2014-12-02 Takeda Pharmaceutical Company Limited Compounds for suppressing a peripheral nerve disorder induced by an anti-cancer agent
US9518062B2 (en) 2009-07-16 2016-12-13 Mallinckrodt Llc Compounds and compositions for use in phototherapy and in treatment of ocular neovascular disease and cancers

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4409671C1 (de) * 1994-03-15 1995-03-23 Detlef Dr Preiss Verwendung von 2-Methylamino-2-phenylcyclohexanon zur Behandlung von Bakterien-, Pilz-, Virus-, oder Protozoeninfektionen und zur Immunmodulation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACT, Vol. 113 (1990), NUGLISCH et al. entire Abstract. *
See also references of EP0557290A4 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014441A1 (fr) * 1992-12-22 1994-07-07 Aktiebolaget Astra Utilisation d'une dihydropyridine enantiomere
WO1994025029A3 (fr) * 1993-04-26 1994-12-22 Janssen Pharmaceutica Nv Utilisation de sabeluzole dans le traitement de maladies neurodegeneratives chroniques
US5691201A (en) * 1993-04-26 1997-11-25 Janssen Pharmaceutica, N.V. Use of sabeluzole in chronic neurodegenerative diseases
WO1994027602A1 (fr) * 1993-06-01 1994-12-08 Cortex Pharmaceuticals, Inc. Utilisation d'agonistes des recepteurs metabotropiques pour le traitement de neurodegenerescences evolutives
US5622981A (en) * 1993-06-01 1997-04-22 Cortex Pharmaceuticals, Inc. Use of metabotropic receptor agonists in progressive neurodegenerative diseases
EP0664127A2 (fr) * 1993-12-28 1995-07-26 Nippon Zoki Pharmaceutical Co., Ltd. Composition pharmaceutiques contenant des dérivés de l'isoquinoline
EP0664127A3 (fr) * 1993-12-28 1999-12-29 Nippon Zoki Pharmaceutical Co., Ltd. Composition pharmaceutiques contenant des dérivés de l'isoquinoline
EP0698391A1 (fr) * 1994-07-29 1996-02-28 Synthelabo Utilisation de l'ifenprodil et de ses diastéréoisomères pour la préparation de médicaments utiles dans le traitement des neuropathies périphériques et des maladies neurodégénératives centrales
US5543421A (en) * 1994-07-29 1996-08-06 Synthelabo Method of treatment of peripheral neuropathies and central neurodegenerative diseases
WO1997033582A1 (fr) * 1996-03-14 1997-09-18 Synthelabo Compositions d'antagonistes de site polyamine
WO2002062795A3 (fr) * 2001-02-02 2003-05-30 Mitsubishi Pharma Corp Composes de dihydropyrazolopyridine et leur utilisation pharmaceutique
US6977262B2 (en) 2001-02-02 2005-12-20 Mitsubishi Pharma Corporation Dihydropyrazolopyridine compounds and pharmaceutical use thereof
US7732467B2 (en) 2003-05-15 2010-06-08 Alzheimer's Institute Of America, Inc. Method for reducing amyloid deposition, amyloid neurotoxicity and microgliosis
US8236347B2 (en) 2007-10-05 2012-08-07 Alzheimer's Institute Of America, Inc. Pharmaceutical compositions for reducing amyloid deposition, amyloid neurotoxicity, and microgliosis
US8236346B2 (en) 2007-10-05 2012-08-07 Alzheimer's Institute of America, Inc Method for reducing amyloid deposition, amyloid neurotoxicity, and microgliosis with (-)-nilvadipine enantiomer
US9518062B2 (en) 2009-07-16 2016-12-13 Mallinckrodt Llc Compounds and compositions for use in phototherapy and in treatment of ocular neovascular disease and cancers
US9527858B2 (en) 2009-07-16 2016-12-27 Mallinckrodt Llc Compounds and compositions for use in phototherapy and in treatment of ocular neovascular disease and cancers
US8901171B2 (en) 2010-01-27 2014-12-02 Takeda Pharmaceutical Company Limited Compounds for suppressing a peripheral nerve disorder induced by an anti-cancer agent
US20130053411A1 (en) * 2010-05-03 2013-02-28 Tsh Biopharm Corporation Ltd. Pharmaceutical composition and method for treating hypertension
AU2011250485B2 (en) * 2010-05-03 2016-07-07 Tsh Biopharm Corporation, Limited Pharmaceutical composition and method for treating hypertension
US9744165B2 (en) 2010-05-03 2017-08-29 Tsh Biopharm Corporation Ltd. Method for treating hypertension

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EP0557290A4 (fr) 1993-07-14
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