Abstract: Prolonged administration of subanesthetic dosages of ketamine, which suppresses activity at NMDA receptors, can provide a damaged central nervous system with an opportunity to use its innate healing processes to “reset” NMDA receptors which were pushed into an unwanted hyper-sensitized state by unusually high activity. However, such treatments can cause permanent brain damage, if the ketamine dosage is too heavy or prolonged. Certain types of “safener” drugs have previously been identified, which can block or at least reduce those unwanted side effects. It is disclosed that if two classes of safener drugs are combined, which will simultaneously suppress activity at both (i) muscarinic acetylcholine receptors, and (ii) the kainate and AMPA classes of glutamate receptors, those safener drug combinations can provide exceptionally potent and reliable safening activity, which can enable the safe use of potent NMDA antagonist drugs for a number of highly beneficial purposes.

Abstract: By disrupting a natural process used by developing mammalian brains to prune and delete surplus neurons, surgical anesthetics and other drugs that suppress brain activity in fetuses and infants can trigger permanent pathological brain damage. That type of damage can be prevented by drug interventions that block one or more “upstream” events that otherwise would lead to the release of “Cytochrome C”, a messenger molecule that triggers apoptosis (programmed cell death) among immature neurons. Lithium is a potent protective agent that can be coadministered along with ketamine or other NMDA-acting or GABA-acting anesthetics and anticonvulsants. Xenon gas triggers only mild damage, and can enable improved anesthesia when combined with other drugs. Other protective drugs (also called safener drugs), and treatments that can prevent or minimize fetal alcohol syndrome, also are disclosed.

Abstract: This invention discloses that a combination of two drugs, from two different and previously unrelated categories, provides effective and long-lasting relief from neuropathic pain. Both drugs can be taken orally, in a convenient, painless, non-invasive manner that does not require injections. One drug in this combination is an &agr;2 adrenergic agonist, exemplified by clonidine. The other drug in the pain-relieving combination has a tri-cyclo-alkyl-amine (TCAA) structure. At least some TCAA drugs have antagonist (receptor-blocking) activity at two entirely different classes of neuronal receptors: the muscarinic subclass of acetylcholine (ACh) receptors, and the NMDA subclass of glutamate receptors. Such drugs include ethopropazine, normally used as an anti-cholinergic drug, and desipramine, normally used as an anti-depressant.

Abstract: This invention discloses that a combination of two drugs, from two different and unrelated categories, provides effective and long-lasting relief from neuropathic pain. Both drugs can be taken orally, in a convenient, painless, non-invasive manner that does not require injections. One drug is an aryl-cyclo-alkanolamine (ACAA) which has antagonist (receptor-blocking) activity at the NMDA subclass of glutamate receptors; such drugs include procyclidine, biperiden, and trihexyphenidyl. The other drug is an &agr;2 adrenergic agonist, exemplified by clonidine. When an ACAA drug which blocks NMDA receptors, such as procyclidine, is administered together with an &agr;2 adrenergic agonist such as clonidine, these drugs mutually potentiate one another's neuropathic pain-relieving action, and provide potent and sustained neuropathic pain relief, even when each agent is administered at a low dosage that is below its threshold for causing adverse side effects.

Abstract: A method of treating Alzheimer's disease is disclosed, not just with palliatives, but in a manner that prevents the progressive degeneration caused by Alzheimer's disease. Certain types of “safener” drugs, which can reduce the neurotoxic damage caused by a potent NMDA antagonist drug such as dizocilpine maleate (also known as MK-801) can also retard the type of corticolimbic damage which, in the brain of a patient who suffers from Alzheimer's disease, results from over-excitation of corticolimbic neurons. This over-excitation is caused or aggravated by NMDA receptor dysfunction in neuronal circuits which normally limit and control excitatory neurotransmitter release within those corticolimbic regions. Safener drugs include various known drugs that can suppress activity at muscarinic acetylcholine receptors, sigma receptors, kainic acid receptors, or AMPA receptors. They also include various drugs which can stimulate activity at alpha-2 adrenergic or 5HT-2A serotonin receptors.

Abstract: A combination of two drugs, from two different and previously unrelated categories, provides effective and long-lasting relief from neuropathic pain. Both drugs can be taken orally, in a convenient, painless, non-invasive manner that does not require injections. One drug in this combination is an &agr;2 adrenergic agonist, exemplified by clonidine. The other drug in the combination is an adamantane derivative which has NMDA antagonist activity, such as memantine. Tests described herein demonstrate that when memantine is administered together with an &agr;2 adrenergic agonist such as clonidine, these drugs mutually potentiate one another's neuropathic pain-relieving action, and provide potent and sustained neuropathic pain relief, even when each agent is administered at a low dosage that is below its threshold for causing adverse side effects.

Abstract: Methods for treating the very early (presymptomatic) stages of Alzheimer's disease are disclosed, wherein NMDA antagonist drugs are administered to protect NMDA receptors against neuronal damage. Since NMDA antagonists may cause a condition known as NMDA receptor hypofunction (NR/hypo) that triggers neurotoxic side effects, they may be co-administered with, or have inherent activity as, "safener" drugs to prevent toxic side effects. The patient's status must be monitored, so that any NMDA antagonist drugs can be discontinued if a condition of NR/hypo arises. Otherwise, the NMDA antagonist drugs can worsen and accelerate the damage caused by the disease.

Abstract: This invention discloses that ibogaine, a plant derivative, can be used safely to treat neuropathic pain (i.e, pain which does not respond conventionally to opiate drugs such as morphine). Ibogaine functions inside the CNS as an NMDA antagonist which is inherently safe, even at relatively high dosages (including dosages high enough to cause hallucinations). Ibogaine does not cause the neurotoxic side effects caused by other NMDA antagonist drugs; this relative safety of ibogaine is due to antagonist activity at neuronal sigma receptors, which had not been known prior to discovery by the Applicant. Ibogaine can also be used for this purpose in combination with additional drugs such as (1) drugs which activate alpha-2 adrenergic receptors; (2) drugs which block the kainic acid subclass of glutamate receptors; or, (3) anti-cholinergic agents that suppress activity at muscarinic acetylcholine receptors. Such drug combinations can reduce or avoid the hallucinatory effects of ibogaine, if desired.

Abstract: This invention relates to a new method for treating or preventing brain damage caused by NMDA receptor hypofunction (NR/hypo), using drugs such as lisuride which stimulate (agonize) activity at the 5HT-2A class of serotonin receptors, but which do not cause hallucinations. Data disclosed herein indicate that stimulation of both 5HT-2A and 5HT-2C receptors causes hallucinations, while stimulation of 5HT-2A receptors but not 5HT-2C receptors does not. Accordingly, to be useful herein, non-hallucinatory 5HT-2A agonists should either (1) antagonize (suppress) activity at 5HT-2C receptors, or (2) have no significant effect on activity at 5HT-2C receptors. Selective non-hallucinatory 5HT-2A agonists can be used in either of two treatment methods disclosed herein.One such treatment comprises administering a 5HT-2A receptor agonist as a "safener drug" which accompanies an NMDA antagonist drug that is being used for a therapeutic purpose.

Abstract: A method for reducing progressive neuronal degeneration due to Alzheimer's disease is disclosed wherein a neuroprotective drug selected from the group consisting of clozapine, olanzapine and fluperlapine, and salts, isomers and analogs thereof, is administered.

Abstract: This invention involves a pharmaceutical mixture for preventing or reducing excitotoxic brain damage caused by hypoxia/ischemia (such as stroke) and various other factors. This mixture comprises an NMDA antagonist and a non-NMDA antagonist, both of which penetrate blood-brain barriers (BBB's) and which, in combination, provide greater protection against excitotoxic damage than can be provided by any quantity of either agent by itself. Suitable NMDA antagonists can be either competitive antagonists which bind directy to the NMDA binding site in the NMDA receptor complex, or non-competitive agents that interact with other binding sites such as the PCP, glycine, or polyamine binding sites. Suitable non-NMDA antagonists include a quinoxalinedione compound referred to as NBQX, and a 2,3-benzodiazepine compound referred to as GYKI 52466.

Abstract: This invention discloses that kainic acid receptor antagonists (KA antagonists) can act as "safener" agents to reduce or prevent adverse side effects caused by NMDA antagonists. NMDA antagonists can reduce excitotoxic brain damage due to stroke, cardiac arrest, asphyxia, etc., but they also cause toxic damage to certain types of neurons, as well as psychotomimetic effects such as hallucinations. Co-administration of a KA antagonist can (1) reduce or prevent such undesired side effects, and (2) increase the extent of neuronal protection provided to the CNS, beyond the levels of protection that can be provided by NMDA antagonists alone, or non-NMDA antagonists alone. Therefore, co-administration of a KA antagonist allows NMDA antagonists to be used more safely and effectively.

Abstract: This invention discloses that ibogaine, a plant derivative, can be used as a safe NMDA antagonist at relatively high dosages (including dosages high enough to cause hallucinations), to reduce or prevent excitotoxic brain damage due to stroke, cardiac arrest, trauma or other forms of neuronal injury or degeneration, without causing the neurotoxic side effects caused by other NMDA antagonist drugs. The relative safety of ibogaine is due to antagonist activity at neuronal sigma receptors, which had not been known prior to discovery by the Applicant. This invention also discloses that ibogaine also can be administered in combination with (1) drugs that suppress activity at muscarinic acetylcholine receptors, or (2) drugs which suppress activity at the kainic acid subclass of glutamate receptors, to reduce or avoid the hallucinatory effects of ibogaine and provide a higher level of neuroprotective activity.

Abstract: This invention discloses mixtures of NMDA antagonists and anti-cholinergic agents, which can be used to prevent excitotoxic damage in the central nervous system or for anesthetic purposes in human or veterinary medicine. Anti-cholinergic agents such as scopolamine, atropine, benztropine, trihexyphenidyl, biperiden, procyclidine, benactyzine, or diphenhydramine can be used in conjunction with, or subsequent to, administration of an NMDA antagonist such as MK-801. The NMDA antagonist exerts a primary protective effect by preventing or reducing excitotoxic damage due to stroke, perinatal asphyxia, and various other types of injury or disease; however, strong NMDA antagonists such as MK-801 can also cause neurotoxic side effects, including vacuole formation, mitochondrial dissolution, and neuronal death in certain types of neurons such as cingulate/retrosplenial cerebrocortical neurons.

Abstract: Methods and compositions are disclosed for treating or preventing adverse CNS effects produced by NMDA receptor hypofunction (NRH), including hypofunction induced by NMDA antagonist drugs, and hypofunction occurring as a causative or aggravating factor in schizophrenia. One method of this invention comprises administering an alpha-2 adrenergic (.alpha.2) receptor agonist drug along with an NMDA antagonist drug. The NMDA antagonist drug exerts a primary benefit in reducing excitotoxic brain damage, alleviating neuropathic pain, or preventing or avoiding tolerance or addiction to various types of drugs. The .alpha.2 agonist drug acts as a secondary or "safener" drug, to prevent the neurotoxic side effects that would be caused by the NMDA antagonist in the absence of the safener drug. Another method disclosed herein involves the use of an .alpha.

Abstract: Certain barbiturates have been shown to completely prevent the neurotoxic injury to cerebrocortical neurons that can be caused by NMDA antagonists. The use of barbiturates as "safening agents" allows NMDA antagonists (including powerful NMDA antagonists such as MK-801) to be used safely as neuroprotectants to prevent brain damage due to hypoxia/ischemia caused by strokes, cardiac arrest, perinatal asphyxia, and various other conditions.

Abstract: This invention discloses a method of using a salt of pyruvic acid (such as sodium pyruvate) to protect against neuronal degeneration due to ischemia (inadequate blood flow, which can be caused by stroke, cardiac arrest, or other events) or due to hypoxia, hypoglycemia, or cellular disorders which interfere with the energy metabolism of neurons. Treatment with pyruvate can be effective even when administered after the onset of an event that triggers neurodegeneration. A preferred mode of use involves co-administration of a pyruvate salt along with one or more agents that block NMDA and/or non-NMDA receptors, or with insulin or a thrombolytic agent.

Abstract: This invention relates to a method and a class of pharmaceutical agents for suppressing vomiting, nausea, and other emetic symptoms. The method involves administering to a susceptible mammal a glutamate (EAA) receptor antagonist at an anti-emetically effective dose which does not cause undesirable side effects. Preferred EAA antagonists include those that do not readily cross blood-brain barriers (BBB). One suitable formulation comprises a broad-spectrum antagonist such as kynurenic acid or 7-chlorokynurenate. Other formulations include EAA antagonists that preferentially block NMDA receptors (such as D-AP5) or non-NMDA receptors (such as CNQX), or mixtures thereof that can block both classes of EAA receptors. In lab tests, the agents of this invention were shown to reduce or entirely block the effects of several emetic agents, including cisplatin.

Abstract: A compound and method are disclosed for reducing the effects of epilepsy, especially temporal lobe epilepsy. The treatment disclosed by the subject invention is provided by administering an aryl-cycloalkyl-alkanolamine substance having the general formula: ##STR1## The compounds procyclidine, biperiden, and trihexyphenidyl fall within this class of compounds. Although not previously recognized to be effective against epilepsy, all three representative compounds were tested against soman and pilocarpine, two cholinergic neurotoxins used in animal research on epilepsy. All three of those compounds were shown to be highly effective in providing protection against the seizures and neurological damage caused by cholinergic neurotoxins, even when administered only after the onset of convulsions.

Abstract: This invention involves a method for reducing neurotoxic side effects that can be caused when NMDA antagonists such as MK-801 are used as anti-convulsants, to prevent excitotoxic damage in the central nervous system, or for anesthetic purposes in human or veterinary medicine. This method involves the use of anti-cholinergic agents such as scopolamine, atropine, benztropine, trihexyphenidyl, biperiden, procyclidine, benactyzine, or diphenhydramine in conjunction with, or subsequent to, administration of an NMDA antagonist. These anti-cholinergic agents greatly reduce or eliminate the deleterious side effects that can accompany NMDA antagonists (such as convulsion potentiating effects, as well as vacuole formation, mitochondrial dissolution, and possible death of cingulate/retrosplenial cerebrocortical neurons), without interfering with the useful properties of the NMDA antagonists.