EP0949915A1 - Traitement de la demence associee a l'infection par le virus du sida (vih-1) au moyen de pieges a radicaux libres a base de nitrone - Google Patents

Traitement de la demence associee a l'infection par le virus du sida (vih-1) au moyen de pieges a radicaux libres a base de nitrone

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Publication number
EP0949915A1
EP0949915A1 EP97920402A EP97920402A EP0949915A1 EP 0949915 A1 EP0949915 A1 EP 0949915A1 EP 97920402 A EP97920402 A EP 97920402A EP 97920402 A EP97920402 A EP 97920402A EP 0949915 A1 EP0949915 A1 EP 0949915A1
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EP
European Patent Office
Prior art keywords
pbn
nitrone
active agent
adc
free radical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97920402A
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German (de)
English (en)
Other versions
EP0949915A4 (fr
Inventor
Robert Floyd
William Garland
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Oklahoma Medical Research Foundation
Centaur Pharmaceuticals Inc
Original Assignee
Oklahoma Medical Research Foundation
Centaur Pharmaceuticals Inc
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Application filed by Oklahoma Medical Research Foundation, Centaur Pharmaceuticals Inc filed Critical Oklahoma Medical Research Foundation
Publication of EP0949915A1 publication Critical patent/EP0949915A1/fr
Publication of EP0949915A4 publication Critical patent/EP0949915A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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

Definitions

  • This invention relates to the treatment of dementia associated with AIDS virus (HIV-1) infection. More particularly it concerns compositions and methods for prophylactically or therapeutically treating this condition.
  • HIV-1 AIDS virus
  • This Background Information section is divided into two parts. The first provides information on the condition being treated by this invention, the dementia associated with AIDS virus infection. The second provides information concerning nitrone-based free radical trapping compounds and their use as medicaments, such compounds being the active agents employed in the methods and compositions of this invention.
  • AIDS Acquired Immune Deficiency syndrome
  • ADC AIDS Dementia Complex
  • HV-associated dementia As many as 50% of infected children have neurological deficits manifested as delayed developmental milestones.
  • Neurological diseases associated with HIV infection include myelopathy, peripheral neuropathy and myopathy.
  • the neuropathological alterations that accompany HIV infection in the CNS include myelin pallor, increased astrogliosis, neuronal loss, and loss of dendritic arborization as well as a decrease in the presynaptic area. Resulting neurologic dysfunction can impair daily function, work productivity and in severe cases mandate expensive institutional care. Although early losses in mental capacity are not considered full-blown dementia, they nevertheless reflect neuronal damage associated with HIV-1. At present there are no effective therapies for AIDS-dementia or HIV-associated dementia. The medicaments described herein minimize the neuronal damage and prevent the progression of neuronal damage thus allowing extended functional capabilities of the affected individuals and hence considerable savings to society.
  • the envelope glycoprotein of HIV, gpl20 has been implicated in the pathogenesis of ADC.
  • This protein which is shed abundantly by infected cells, has been found to be neurotoxic to neurons in culture at extremely low concentrations, to impair learning, to induce cytokines, and to reduce cerebral glucose utilization.
  • Hill et al. (.Hill, J.M. , Mervis, R.R. , Avidor, R. , Moody, T.W. and Brenneman, D.E. (1993) Brain Res . , 603:222-233.) have shown that in neonatal rats, administration of gpl20 causes morphological damage to the brain as well as retardation of the development of complex motor behaviors.
  • the NO generated from the nitroglycerin can protect neurons from overstimulation of the NMDA receptors with the resulting calcium and glutamate excitotoxicity.
  • cardiovascular effects and the extremely erratic pharmacokinetics of nitroglycerin make this approach seem problematic.
  • Neuropathology associated with ADC has been postulated to be mediated by nitric oxide (NO) , among other factors.
  • Dawson et al. (Dawson, V.L., Dawson, T.M., Uhl, G.R., and Synder, S.H. (1993) Proc. Natl . Acad . Sci . USA, 90:3256-3259) demonstrated that in a rat cortex neuronal culture, gpl20-mediated killing of neurons was due to generation of NO.
  • the evidence supporting this conclusion was that neuronal killing was prevented by L-arginine depletion as well as by addition of nitroarginine, conditions expected to inhibit NO production by nitric oxide synthase (NOS) .
  • NOS nitric oxide synthase
  • Mollace et al (Mollace, V., Colasanti, M. , Persichini, T., Bagetta, G., Lauro, G.M. and Nistico, G. (1993) Biochem . Biophys . Res . Commun . , 194:439-445.) demonstrated that gpl20 addition to human T67 astrocytoma cell caused large increases in NO formation, which was found to be due to the activity of the inducible isoform of the enzyme, iNOS. Antibodies to gpl20 were shown to prevent iNOS induction and NO formation.
  • Nitrone-Based Free Radical Trapping Compounds as Medicaments This invention's approach to mitigating ADC employs nitrones and nitrone-related analogues as the active agent, in particular nitrone-based free radical trapping compounds.
  • the best known and most widely studied nitrone is ⁇ -phenyl-t-butyl nitrone (PBN) .
  • Another well known nitrone is ⁇ -(4-pyridinyl-l-oxide)N- tert-butyl nitrone (POBN) .
  • nitrones Before any pharmaceutical use was made of nitrones, they were used as analytical tools capable of reacting with highly reactive radicals to yield free radical adducts that are much less reactive. In many cases, the free radical/NRT adduct complex is stable enough to allow in vivo isolation and quantitation using electron spin resonance (ESR) .
  • ESR electron spin resonance
  • the use of nitrones as therapeutics in neurological diseases is reported, for example, in United States Patent Nos. 5,025,032, 5,036,097; 5,405,874; 5,475,032; 5,488,145; 5,508,305; 5,578,617; and published PCT patent applications US91/05552 and WO 92/22290.
  • Nitrones have been shown, when administered chronically, to reverse the age-associated increase in oxidatively damaged protein and the age-associated decrease in the activity of the oxidative-sensitive enzyme, glutamine synthetase (GS) in the brain.
  • GS glutamine synthetase
  • NRTs nitrone-based free radical trapping compounds
  • the present invention in one embodiment comprises a pharmaceutical composition comprising an effective AIDS dementia complex-treating amount of a nitrone- based free radical trapping compound in a pharmaceutically acceptable carrier.
  • the present invention in another embodiment comprises a method for treating a patient afflicted with AIDS dementia complex. This method involves administering an effective AIDS dementia-treating therapeutic dose of a nitrone-based free radical trapping compound to a patient in need of such therapy.
  • the present invention also comprises a method for prophylaxis for a patient likely to become afflicted with AIDS dementia complex. This method involves administering an effective AIDS dementia-preventing prophylactic dose of a nitrone-based free radical trapping compound to a patient identified as being in need of such prophylaxis.
  • NO nitric oxide
  • the method of treatment of this invention employs one or more nitrone-based free radical trapping compounds as its active agent.
  • PBN ⁇ -phenyl butyl nirone
  • PBN ⁇ -phenyl butyl nirone
  • POBN 4-pyridinyl-l- oxide
  • POBN 4-pyridinyl-l- oxide
  • derivatives thereof also find application here.
  • Derivatives of these materials may also be used, including by way of example but not being limited to hydroxy derivatives, especially 2-, 3- or 4-hydroxyphenyl t-butyl nitrone and phenyl (mono-, di- or trihydroxy) tert-butyl nitrone; PBN esters, especially esters which release 2- , 3-, or 4-hydroxyphenyl t-butyl nitrone such as acetoxy derivative; 2-, 3-, or 4-carboxyphenyl t-butyl nitrone; phenyl hydroxybutyl nitrone; alkoxyl derivatives, especially alkoxyl derivatives which release 2-, 3-, or 4-hydroxyphenyl t-butyl nitrone, for example, the 2-, 3-, or 4-methoxyphenyl derivatives of PBN; and acetamide derivatives such as those related to 2-, 3-, or 4-aminophenyl t-butyl nitrone; diphenyl nitrone (
  • POBN derivatives may also be employed. It will be appreciated that some of these materials can exist as pharmaceutically acceptable salts as well as the compounds described above. In the case of salts the materials will be ionized and accompanied by a pharmaceutically acceptable anion or cation as appropriate.
  • a cation is a monovalent material such as sodium, potassium or ammonium, but it can also be a multivalent cation in combination with a pharmaceutically acceptable monovalent anion, for example calcium with a chloride, bromide, iodide, hydroxyl, nitrate, sulfonate, acetate, tartrate, oxalate, succinate, palmoate or the like anion; magnesium with such anions; zinc with such anions or the like.
  • a pharmaceutically acceptable monovalent anion for example calcium with a chloride, bromide, iodide, hydroxyl, nitrate, sulfonate, acetate, tartrate, oxalate, succinate, palmoate or the like anion; magnesium with such anions; zinc with such anions or the like.
  • NRT nitrone-based free radical trap
  • X is phenyl, imidazolyl, phenothiazinyl,
  • R independently (can vary within the molecule) halogen, alkenyl, oxyalkenyl, oxyalkyl, OH, NH 2 , NHZ,
  • NZ 2 NO, -SO 3 H, -OSO 3 H, -S(alkyl) , -S(alkenyl), haloalkyl (including CF 3 ) , Z,
  • A is 0 or S
  • Z is a C 1-6 straight or branched alkyl or cyclic group
  • n is a whole integer from 1 to 5 (preferably 1 to 3)
  • Y is a tert-butyl group that can be hydroxylated or acetylated on one or more positions; phenyl; or the moiety
  • R and n are as defined above, and
  • Z is a C j to C 5 straight or branched alkyl group.
  • spin-trapping agents can also be used, such as ⁇ -(4-pyridyl 1-oxide) -N-tertbutylnitrone (POBN), and spin-trapping derivatives thereof.
  • Derivatives are made using standard techniques, for example, for substitution of the methyl groups.
  • the general formula for P O BN and exemplary derivatives thereof is the following:
  • Y is a tert-butyl group that can be hydroxylated or acetylated on one or more positions; phenyl; or
  • n is a whole number from 1 to 4 , or
  • Z is a C x to C 5 straight or branched alkyl group.
  • the nitrone-based free radical trapping compound may be formulated into pharmaceutical compositions suitable for oral or parenteral, e.g. intravenous or intramuscular injection, administration.
  • compositions for oral administration can take the form of liquid solutions or suspensions, powders, tablets, capsules or the like.
  • the nitrone or its salt is usually a minor component (0.1 to 50% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • a liquid form may include a suitable aqueous or nonaqueous vehicle with buffers, suspending dispensing agents, colorants, flavors and the like.
  • a solid form may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, sugar, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • injectable compositions they are commonly based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. Again the active nitrone is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • sustained release materials can be found in the referenced materials in Remington's Pharmaceutical Sciences.
  • the conditions treated with the nitrone-based free radical trapping compound-containing compositions generally include ADC and the various symptoms which fall within the ADC definition.
  • the nitrone-based formulations can be administered to achieve a therapeutic effect and slow or counteract the progression of ADC. Alternatively, the formulations can be administered prophylactically to patients not yet exhibiting ADC but exposed to the HIV-1 virus.
  • the nitrone-containing composition is administered in a manner designed to get the drug into the patient's bloodstream and across the blood-brain barrier into the patient's brain. One excellent mode for accomplishing this is intravenous administration.
  • Intravenous dose levels for treating these conditions range from about 0.01 mg/kg/hour to about 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 1 to 96 hours.
  • a preloading bolus of from about 10 to about 500 mg may also be administered to achieve adequate steady state levels.
  • Other forms of parenteral administration, such as intramuscular injection can be used, as well. In this case, similar dose levels are employed. While parenteral administration is attractive from a drug delivery point of view, it should be recognized that the course of AIDS infection can stretch over many months or even years. As a result, oral dosing may be preferred for patient convenience and tolerance.
  • Example 1 PBN is admixed as a dry powder with a dry gelatin binder in an approximate 1:10 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (20-30 mg of active nitrone) in a tablet press. These tablets may be administered to a patient suffering from ADC or and ADC-related condition on a daily, twice daily or thrice daily regimen.
  • a PBN ester is admixed as a dry powder with a starch diluent in an approximate 1:4 weight ratio.
  • the mixture is filled into 250 mg capsules (50 mg of active nitrone-based free radical trapping compound.) These capsules may be administered to a patient suffering from a ADC-associated condition on a daily, twice daily or thrice daily regimen.
  • Example 3 The nitrone, POBN, is admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 450-900 mg tablets (150-300 mg of active nitrone-based free radical trap) in a tablet press. These tablets may be administered to a patient suffering from a HIV infection on a daily, twice daily or thrice daily regimen.
  • Example 4 PBN is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml. 50 mis of this liquid material may be administered to a patient suffering from ADC on a daily, twice daily or thrice daily regimen.
  • any of the nitrone compounds described herein may be employed in any of these representative formulations, and that any of these formulations may be administered in any manner so as to treat or protect against ADC.
  • TNF- ⁇ (100 pg/ml) was used as the neurotoxin and the length of incubation was 72 hours.
  • TNF- ⁇ is one of the neurotoxins responsible for HIV Dementia. Brain concentrations of TNF- ⁇ are elevated in deep grey matter from AIDS patients with mold HIV Dementia.
  • TNF- ⁇ messenger RNA expressing TNF- ⁇ in the brain follows a similar pattern.
  • Gelbard et al. have shown that HIV-1 infected monocytes in culture with astroglial cells produce concentrations (>200 pg/ml) of TNF- ⁇ sufficient to cause neurotoxicity.
  • TNF- ⁇ is reported to cause its neurotoxicity by inducing apoptosis.
  • gpl20 exerts toxic effects through induction of IL-6 and TNF- ⁇ .
  • Brain cell aggregates were prepared from second trimester abortion tissue. Briefly, human brain tissue between 16 and 18 weeks gestation are gently dissociated through nylon screens to obtain single cells. Approximately 4X10 7 cells within 4 ml DME supplemented with 0.6% dextrose, 50 mg/ml gentamicin and 10% FCS are distributed into 25 ml DeLong flasks. Aggregates are constantly rotated and incubated at 37°C in an atmosphere of 10% C0 2 . After 2-3 days, aggregates are transferred to 50 ml flasks and 5 ml of DME supplemented with 15% FCS (exchange medium) added. Each flask contains several thousand aggregates that can be sampled over time. Five ml of medium is exchanged every other day in culture.
  • Brain cell aggregates are differentiated at the time of sampling in that they express neural cell markers for identification. Brain cell aggregates contain all the cells of the CNS (approximately 40% neurons, 40% astrocytes, 10% oligodendrocytes and myelin and 10% microglia) . Neural cell apoptosis/death was measured by DNA fragmentation Elisa technique according to manufacturer's directions (Boehringher Mannheim) at a concentration of 10 micromolar.
  • Brain aggregates were prepared as described above. Several aggregates are placed in each well of a multi- well chamber slide (Nunc) coated with Cell TAK (collaborative Research) at a concentration of 20 ug/ml. Cells migrate from the brain aggregates within 3 days. Astrocytes form a monolayer with neurons on top and rare microglia ( ⁇ 1%) /oligodentrocytes ( ⁇ 1%) . These cultures are confluent within 1 week. Monolayers can be maintained for up to three weeks.
  • Characterization of cell types is determined by using immunohistochemistry and the antibodies neuron specific enolase (NSE, Dako) for neurons and glial fibrillary acidic protein (GFAP, Dako) for the identification of astrocytes. Confocal microscopy was used to visualize and identify neurons and astrocytes by size and shape. Neuronal viability was determined by exposing chambers with and without different treatments to AO and ethidium bromide (EtBr) . Neurons and total cell counts were determined by AO staining with visual confirmation by phase microscopy. Enumeration of cell viability by computerized software was performed at the time of microscopy. In addition, a visual printout of the fields observed always accompanied the data. The cell viability (programmed cell death/PCD) data from the above tests is summarized at Tables 1-2 below: Table 1
  • Sodium N-methyl D-glucamine dithiocarbamate (MGD) and PBN were obtained from OMRF Spin Trap Source, Oklahoma City, Oklahoma.
  • gpl20 was obtained from Intracel Corporation, Cambridge, Massachusetts.
  • Sprague-Dawley neonatal rats (sixteen siblings) were divided into four groups. Starting at day one after birth until day six, the neonates received 60 ⁇ l subcutaneous injections of the following treatments. Group 1: phosphate buffer-saline (PBS), Group 2: 5 ng gpl20 in PBS, Group 3: 5 ng gpl20 plus PBN (50 mg/kg) in PBS, and Group 4: PBN (50 mg/kg) in PBS. Rats were weighed daily and the amount of PBN injected was adjusted accordingly.
  • PBS phosphate buffer-saline
  • Group 3 5 ng gpl20 plus PBN (50 mg/kg) in PBS
  • PBN 50 mg/kg
  • NO spin trapping Formation of NO in the brain of gpl20 treated rat pups was determined by NO spin trapping.
  • neonates treated as described were injected intraperitoneally with 200 ⁇ l of a sterile saline solution containing 100 mM MGD and 10 mM FeS0 4 .
  • Stock solutions of MGD (200 mM) and FeS0 4 (20 mM) were made separately in derated saline.
  • 100 ⁇ l of each solution was pulled into the same syringe and injection was performed. Rats were decapitated 30 min after administration of MGD-Fe and brains were immediately excised.
  • a sagittal section immediately adjacent to the median plane was transferred onto the EPR tissue cell and the EPR spectrum was recorded using an ESP 300 E Bruker Electron Spin Resonance Spectrometer.
  • the EPR settings were as follows: receiver gain: 5.00 x 10 5 , modulation amplitude: 2.0 gauss, modulation frequency: 100 KHZ.
  • Table 3 shows that gpl20 caused a significant decrease in the time elapsed before the neonates begin to crawl back upward as well as the time required before they righted themselves after being placed on their backs. PBN coadministration with the gpl20 prevented the gpl20-mediated damage. PBN treatment itself appeared not to have effected the response of the neonates in these tests. There were no differences in the weights of the neonates between the groups (data not shown) .
  • ADC is a neurological syndrome characterized by cognitive deficits and motor and behavioral dysfunction.
  • the HIV-l envelope glycoprotein gpl20 has been implicated in the development of ADC. This protein has been shown to be neurotoxic and to cause learning impairment and retardation of the development of complex motor behavior in rat neonates.
  • Nitric oxide has been implicated in the gpl20-induced neurotoxicity.
  • NO was trapped in the brain of neonatal rats by N-methyl-D-glutamine dithiocarbamate-Fe and the NO content measured by electron paramagnetic resonance (EPR) spectroscopy.
  • EPR electron paramagnetic resonance
  • Fig. 1 illustrates a series of spectral traces which demonstrate the intervention of nitrone-based free radical traps in the production of nitric oxide generated by the action of gpl20.
  • spectral traces illustrating nitric oxide generation in the rat neonate brain determined by in vivo EPR NO trapping.
  • Trace A illustrates PBS (60 ⁇ L) administration for 6 consecutive days.
  • Trace B illustrates gpl20 (60 ⁇ L, 83.3 ng/ml) administration for 6 consecutive days.
  • Trace C illustrates gpl20 (60 ⁇ L, 83.3 ng/ml) plus PBN (50 mg/kg) administration for 6 consecutive days.
  • Fig. 1 clearly shows that the gpl20 treatment caused the production of NO in the brain of the treated animals. The NO was trapped by MGD-Fe complex. The triplet signal in the middle spectrum is quite apparent.
  • PBN treatment prevents NO formation in the gpl20-treated animals.
  • Nitric oxide was not trapped in the PBN-treated controls or in the PBN-only treated animals (data not shown) .
  • the amount of NO trapped in the brain of the gpl20-treated animals was estimated to be 5-10 ⁇ M based on past experiments. It should be noted that the spectra presented consists of only one animal each as shown in each case, but the other animals examined gave results consistent with those presented here. These results clearly demonstrate that systemic administration of gpl20 to neonatal rats (6 days) resulted in the formation of NO in the brain of these animals as shown by EPR spin trapping method. While several investigators have reported on gpl20-induced NO formation in cell culture, this is believed to be the first report on the in vivo gpl20-mediated NO generation.
  • the inventors have found high levels of iNOS mRNA following treatment of a rat mixed neuronal/glial cell culture with gpl20. Therefore, the NO detected in the brains of the gpl20 rat neonates is most likely due to iNOS induction, which is prevented by PBN coadministration.
  • the dementia observed in individuals infected with ADC or HIV-1 is believed to be due to NO mediated killing of CNS neurons.
  • the viral envelope protein gpl20 has been shown to cause neural damage in a variety of neuronal preparations including rat cortical neurons and rat hippocampal cultures at very low concentrations (picomolar levels) .
  • Glowa et al have demonstrated that intraventricular injections of gpl20 into rats result in behavioral deficits as well as dystrophic neurites in hippocampal pyramidal cells. Similarly, Hill et al have reported developmental retardation in neonatal rats follow systemic gpl20 administration. Expression of gpl20 in the CNS of transgenic mice by Toggas et al caused a spectrum of neuronal and glial changes resembling abnormalities in brain of HIV-1-infected humans. All these results indicate that gpl20 plays a key role in HIV-1-mediated nervous system impairment. ADC is associated with elevated brain cytokine levels.
  • cytokines especially IL-1 and TNF- ⁇ by HIV-1 as well as gpl20
  • Increased release of cytokines has been shown to result in the induction of iNOS through activation of nuclear factor-kappa B (NF- K B) .
  • Reactive oxygen species ROS
  • the preventive action of PBN in the formation of NO in the model studied may be due to the ability of this compound to prevent the rapid rise in ROS which is associated with increased cytokine level and the subsequent iNOS induction.

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Abstract

L'invention concerne des pièges à radicaux libres à base de nitrone, qui sont utiles en tant qu'agents thérapeutiques et prophylactiques dans le traitement de lésions des cellules nerveuses associées à l'infection par le virus HIV-1, connues à des stades plus avancés sous le nom de démence associée à l'infection par le virus du sida, ou complexe de démence liée au sida.
EP97920402A 1996-04-17 1997-04-17 Traitement de la demence associee a l'infection par le virus du sida (vih-1) au moyen de pieges a radicaux libres a base de nitrone Withdrawn EP0949915A4 (fr)

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US1570996P 1996-04-17 1996-04-17
US15709P 1996-04-17
PCT/US1997/006253 WO1997038683A1 (fr) 1996-04-17 1997-04-17 Traitement de la demence associee a l'infection par le virus du sida (vih-1) au moyen de pieges a radicaux libres a base de nitrone

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EP0949915A1 true EP0949915A1 (fr) 1999-10-20
EP0949915A4 EP0949915A4 (fr) 2001-07-04

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EP (1) EP0949915A4 (fr)
AU (1) AU725432B2 (fr)
CA (1) CA2251800A1 (fr)
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WO1991005552A1 (fr) * 1989-10-17 1991-05-02 Oklahoma Medical Research Foundation Procede et compositions inhibant les troubles associes aux lesions oxydatives des tissus
US5185324A (en) * 1988-12-14 1993-02-09 Hoechst Aktiengesellschaft Enzyme-inhibiting amino acid derivatives, a process for the preparation thereof, agents containing these, and the use thereof
US5314917A (en) * 1991-03-22 1994-05-24 E. B. Michaels Research Associates, Inc. Method for inactivating enveloped viruses and sperm

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Publication number Priority date Publication date Assignee Title
US5488145A (en) * 1993-12-23 1996-01-30 Oklahoma Medical Research Foundation 2,4-disulfonyl phenyl butyl nitrone, its salts, and their use as pharmaceutical free radical traps

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Publication number Priority date Publication date Assignee Title
US5185324A (en) * 1988-12-14 1993-02-09 Hoechst Aktiengesellschaft Enzyme-inhibiting amino acid derivatives, a process for the preparation thereof, agents containing these, and the use thereof
WO1991005552A1 (fr) * 1989-10-17 1991-05-02 Oklahoma Medical Research Foundation Procede et compositions inhibant les troubles associes aux lesions oxydatives des tissus
US5314917A (en) * 1991-03-22 1994-05-24 E. B. Michaels Research Associates, Inc. Method for inactivating enveloped viruses and sperm

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EP0949915A4 (fr) 2001-07-04
AU2460697A (en) 1997-11-07
AU725432B2 (en) 2000-10-12
CA2251800A1 (fr) 1997-10-23
WO1997038683A1 (fr) 1997-10-23

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