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1.
J Infect Dis ; 180(4): 1282-7, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10479159

ABSTRACT

WR 238605 is an 8-aminoquinoline developed for the radical cure of Plasmodium vivax. Forty-four P. vivax-infected patients were randomly assigned to 1 of 4 treatment regimens: 3 groups received a blood schizonticidal dose of chloroquine followed by WR 238605: group A (n=15) received 300 mg daily for 7 days; group B (n=11), 500 mg daily for 3 days, repeated 1 week after the initial dose; group C (n=9), 1 dose of 500 mg. A fourth group (D; n=9) received chloroquine only. Among patients who completed 2-6 months of follow-up (n=23), there was 1 relapse in group B (day 120) and 1 in group C (day 112). Among patients treated with chloroquine only, there were 4 relapses (days 40, 43, 49, and 84). WR 238605 was safe, well tolerated, and effective in preventing P. vivax relapse.


Subject(s)
Aminoquinolines/therapeutic use , Antimalarials/therapeutic use , Chloroquine/therapeutic use , Malaria, Vivax/drug therapy , Malaria, Vivax/physiopathology , Adolescent , Adult , Aminoquinolines/adverse effects , Antimalarials/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Male , Prospective Studies , Recurrence , Thailand
2.
Neuropharmacology ; 31(4): 357-68, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1522953

ABSTRACT

The involvement of the NMDA receptor in the neurotoxicity induced by soman, an organophosphorus compound which irreversibly inhibits cholinesterase, was studied in guinea pigs. The drug MK-801 (0.5, 1 or 5 mg/kg, i.p.) was given as a pretreatment before a convulsant dose of soman or as a posttreatment (30, 100 or 300 micrograms/kg, i.m.) 5 min after the development of soman-induced status epilepticus. Pyridostigmine, atropine and pralidoxime chloride were also given to each subject to counteract the lethality of soman. All subjects that were challenged with soman and given the vehicle for MK-801 (saline) exhibited severe convulsions and electrographic seizure activity. Neuronal necrosis was found in the hippocampus, amygdala, thalamus and the pyriform and cerebral cortices of those subjects surviving for 48 hr. Pretreatment with 0.5 or 1 mg/kg doses of MK-801 did not prevent nor delay the onset of seizure activity but did diminish its intensity and led to its early arrest. At the largest dose (5 mg/kg), MK-801 completely prevented the development of seizure activity and brain damage. Posttreatment with MK-801 prevented, arrested or reduced seizure activity, convulsions and neuronal necrosis in a dose-dependent manner. The NMDA receptor may play a more critical role in the spread and maintenance, rather than the initiation of cholinergically-induced seizure activity.


Subject(s)
Brain/pathology , Dizocilpine Maleate/pharmacology , Soman/toxicity , Status Epilepticus/physiopathology , Amygdala/drug effects , Amygdala/pathology , Amygdala/physiopathology , Animals , Brain/drug effects , Brain/physiopathology , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Dizocilpine Maleate/therapeutic use , Electroencephalography/drug effects , Evoked Potentials/drug effects , Guinea Pigs , Hippocampus/drug effects , Hippocampus/pathology , Hippocampus/physiopathology , Necrosis , Neurons/drug effects , Neurons/pathology , Neurons/physiology , Organ Specificity , Status Epilepticus/prevention & control , Thalamus/drug effects , Thalamus/pathology , Thalamus/physiopathology , Time Factors
3.
Brain Res ; 529(1-2): 277-85, 1990 Oct 08.
Article in English | MEDLINE | ID: mdl-2282497

ABSTRACT

Three commonly used antitussive compounds were tested for their ability to block epileptiform activity recorded extracellularly from hippocampal and olfactory cortex slices maintained in vitro. Antitussives were bath-applied to brain slices either before or after epileptiform activity was induced. Dextromethorphan (DM) prevented electrically evoked epileptiform afterdischarges and arrested spontaneous bursting induced by exposure to added NMDA or to Mg2(+)-free medium. In contrast, caramiphen (CM) and carbetapentane (CB) were effective against epileptiform activity induced by Mg2(+)-free medium, but not by NMDA. Atropine was not effective in blocking epileptiform activity at concentrations 10 times the effective concentration of CM, which has known cholinolytic activity. Our results suggest that all these antitussives exert their anticonvulsant action at the DM binding site. Neither cholinolytic activity nor antagonism of the NMDA receptor-channel complex appears to be necessary for antitussives to prevent or arrest epileptiform activity. DM appears to have a separate NMDA-antagonist property in addition to its actions at the DM site. Our neurophysiological evidence supports the hypothesis that these antitussives have anticonvulsant properties independent of any action at the NMDA receptor-channel complex.


Subject(s)
Antitussive Agents/pharmacology , Epilepsy/physiopathology , Hippocampus/physiology , N-Methylaspartate/pharmacology , Olfactory Bulb/physiology , Animals , Cyclopentanes/pharmacology , Dextromethorphan/pharmacology , Electric Stimulation , Evoked Potentials/drug effects , Guinea Pigs , Hippocampus/drug effects , Hippocampus/physiopathology , In Vitro Techniques , Magnesium/pharmacology , Olfactory Bulb/drug effects , Olfactory Bulb/physiopathology
4.
Neurotoxicology ; 11(3): 509-20, 1990.
Article in English | MEDLINE | ID: mdl-2284055

ABSTRACT

The antitussives dextromethorphan (DM), carbetapentane (CBP), and caramiphen (CM) are known to have anti-convulsant properties. They were given individually to guinea pigs prior to poisoning with 2 x LD50 soman to test their efficacy against organophosphorus-induced convulsions, brain damage, and lethality. All subjects received an injection of pyridostigmine coincident with the antitussive, and were treated with atropine methylnitrate and pralidoxime chloride 30 sec after soman administration. CM, in a dose-dependent manner, protected against lethality and either prevented or reduced the intensity of convulsions, electrographic seizure activity (EGSA), and brain damage. CBP delayed the onset of EGSA and reduced its intensity. DM prevented EGSA at higher doses, but neither DM nor CBP protected against the lethal effects of soman. CM is known to possess relatively stronger anticholinergic properties than the other antitussives used in this experiment, which may have contributed to its relatively superior efficacy against soman.


Subject(s)
Antitussive Agents/therapeutic use , Nervous System Diseases/prevention & control , Soman/poisoning , Animals , Anticonvulsants , Cyclopentanes/therapeutic use , Dextromethorphan/therapeutic use , Guinea Pigs , Male , Necrosis , Nervous System Diseases/chemically induced , Nervous System Diseases/pathology , Neurons/pathology , Soman/antagonists & inhibitors
5.
Brain Res Bull ; 23(1-2): 145-8, 1989.
Article in English | MEDLINE | ID: mdl-2553217

ABSTRACT

MK-801, a novel anticonvulsant which is a potent N-methyl-d-aspartate antagonist, attenuated or blocked seizures and convulsions induced by the irreversible organophosphorus anticholinesterase inhibitor soman. Guinea pigs chronically instrumented for electrocorticogram recording were given a low dose (1 mg/kg) or a high dose (5 mg/kg) of MK-801 or saline vehicle 30 min prior to receiving 2 x LD50 of soman. All animals were treated with atropine methylnitrate and pralidoxime chloride 30 sec after soman injection. All saline control subjects exhibited severe seizures and convulsions shortly after receiving soman. Low dose MK-801 greatly attenuated and high dose MK-801 completely blocked seizure activity. Animals treated with MK-801 recovered faster and had a much greater probability of survival for 48 hr after soman exposure than did controls. This is the first demonstration of the involvement of the excitatory amino acid neurotransmitter system in seizures and convulsions induced by a cholinesterase inhibitor.


Subject(s)
Cholinesterase Inhibitors/pharmacology , Convulsants/pharmacology , Dibenzocycloheptenes/pharmacology , Receptors, Neurotransmitter/physiology , Seizures/metabolism , Soman/pharmacology , Animals , Dizocilpine Maleate , Guinea Pigs , Receptors, N-Methyl-D-Aspartate , Seizures/chemically induced , Seizures/physiopathology
6.
Neurotoxicology ; 10(2): 239-47, 1989.
Article in English | MEDLINE | ID: mdl-2559376

ABSTRACT

Transverse slices from guinea pig hippocampi were exposed to micromolar concentrations of sodium cyanide while neural and synaptic function were monitored in the CA1 region. Cyanide concentrations between 10 and 200 microM rapidly depressed synaptic transmission between Schaffer collateral-commissural fibers and CA1 pyramidal cells. Analysis of input/output curves revealed that the suppression had two components, a decrease in EPSP generation and an increase in action potential threshold. Direct electrical excitability of axons was not affected. At concentrations to 500 microM, cyanide had no effect on antidromic activation of pyramidal cells. At 1000 microM, cyanide caused a moderate depression of the antidromic response in one slice while having no effect in one other. In some experiments, postsynaptic responses in the gyrus dentatus (GD), evoked by perforant path stimulation, were recorded simultaneously with CA1 responses during cyanide application. GD was found to be less sensitive to cyanide than CA1. All cyanide effects reversed rapidly and completely upon washout. These findings suggest that cyanide has a direct effect on neurons not mediated by its inhibition of metabolism.


Subject(s)
Cyanides/toxicity , Hippocampus/drug effects , Neurons/drug effects , Sodium Cyanide/toxicity , Synapses/drug effects , Action Potentials/drug effects , Animals , Electric Stimulation , Guinea Pigs , In Vitro Techniques , Synaptic Transmission/drug effects
7.
Neuropharmacology ; 26(9): 1247-51, 1987 Sep.
Article in English | MEDLINE | ID: mdl-2444898

ABSTRACT

Since the neurotoxicity of kainic acid may be due to the opening of membrane channels for calcium ions for (Ca2+), the effects of Ca2+ and other cations were examined on the specific binding of [3H]kainic acid to membranes from the forebrain of the rat. [3H]Kainic acid bound to a high affinity site (KD = 5.6 nM) that was inhibited in a concentration-dependent manner by Ca2+ ions with an IC50 of 3.2 mM. In the presence of 1 mM Ca2+, the KD of the binding of [3K]kainic acid increased to 11.1 nM without any change in the Bmax. The divalent cations, manganese and cobalt, also were potent inhibitors of the binding of [3H]kainic acid, while barium and strontium were much weaker. The inhibitory effects of Ca2+ on the binding of [3H]kainic acid were blocked by the inorganic Ca2+ channel blockers, cadmium and lanthanum. These data suggest that Ca2+ modulates the binding affinity [3H]kainic acid through an allosteric interaction between the binding site on the Ca2+ channel and the kainic acid receptor.


Subject(s)
Calcium/metabolism , Cations, Divalent/pharmacology , Ion Channels/metabolism , Receptors, Neurotransmitter/drug effects , Animals , Brain/metabolism , Calcium/pharmacology , Rats , Rats, Inbred Strains , Receptors, Kainic Acid , Receptors, Neurotransmitter/metabolism , Tritium
8.
Brain Res ; 364(1): 199-203, 1986 Jan 29.
Article in English | MEDLINE | ID: mdl-2868777

ABSTRACT

Olfactory cortex brain slices were subject to multiple bath applications of either glutamate or aspartate. The effectiveness of these amino acids (measured by quantitating the amplitude of lateral olfactory tract-stimulated field potentials) was progressively reduced with each successive perfusion of the agonist. However, the effectiveness of the endogenous neurotransmitter recovered to control in each intervening wash period. Thus, repeated applications of glutamate or aspartate desensitized olfactory cortex receptors to these amino acids but did not desensitize the receptors to the endogenous transmitter. These data support the hypothesis that neither glutamate nor aspartate is the neurotransmitter released from the lateral olfactory tract onto pyramidal cells of the olfactory cortex.


Subject(s)
Aspartic Acid/pharmacology , Glutamates/pharmacology , Limbic System/drug effects , Receptors, Amino Acid , Receptors, Neurotransmitter/drug effects , Animals , Glutamic Acid , In Vitro Techniques , Neuromuscular Junction/drug effects , Neurotransmitter Agents , Olfactory Pathways/drug effects , Receptors, Glutamate
9.
Brain Res ; 307(1-2): 17-28, 1984 Jul 30.
Article in English | MEDLINE | ID: mdl-6466993

ABSTRACT

Unit activity was recorded from the posterior temporal cortex (PTE) of awake, behaving rhesus monkeys while they performed a series of visual discrimination tasks involving colored checkerboard patterns. The activity of 130 (91%) of 143 PTE units was altered by the presentation of a visual discriminandum; 112 of these cells (86%) exhibited a significant increase in firing after presentation of the stimulus while the remainder gave an inhibitory response. Over half (64%) the PTE units exhibited differential activity between discriminanda, i.e. they were selective for color and/or form. Six of 10 neurons, recorded when the monkey was required to shift attention from one stimulus feature to another, exhibited a difference in poststimulus neural activity even though the discriminandum remained the same. Three neurons were recorded from when the stimuli were altered by changing the check size although the relevant (i.e. rewarded) dimension (color) was left the same; two showed an invariant response to the altered stimuli and one gave the same response to one of the altered stimuli but a different response to the other. These data support the role of posterior temporal cortex in visual discrimination learning and visual attention.


Subject(s)
Discrimination Learning/physiology , Temporal Lobe/physiology , Visual Perception/physiology , Animals , Attention/physiology , Brain Mapping , Color Perception/physiology , Electrophysiology , Macaca mulatta , Size Perception/physiology , Water
10.
J Neurophysiol ; 50(6): 1296-311, 1983 Dec.
Article in English | MEDLINE | ID: mdl-6663327

ABSTRACT

Description of the neuronal and synaptic bases of memory in the vertebrate central nervous system (CNS) requires a CNS stimulus-response pathway that is defined and accessible, has the capacity for adaptive change, and clearly contains the responsible substrates. This study was an attempt to determine whether the spinal stretch reflex (SSR), the initial, purely spinal, portion of the muscle stretch response, which satisfies the first requirement, also satisfies the second, capacity for adaptive change. Monkeys prepared with chronic fine-wire biceps electromyographic (EMG) electrodes were trained to maintain elbow position and a given level of biceps background EMG activity against constant extension torque. At random times, a brief additional extension torque pulse extended the elbow and elicited the biceps SSR. Under the control mode, reward always followed. Under the SSR increases or SSR decreases mode, reward followed only if the absolute value of biceps EMG from 14 to 24 ms after stretch onset (the SSR interval) was above or below a set value. Animals performed 3,000-6,000 trials/day over data-collection periods of up to 15 mo. Background EMG and the initial 30 ms of pulse-induced extension remained stable throughout data collection. Under the SSR increases or SSR decreases mode, SSR amplitude (EMG amplitude in the SSR interval minus background EMG amplitude) changed appropriately. Change was evident in 5-10 days and progressed over at least 4 wk. The SSR increased (SSR increases) to 140-190% control amplitude or decreased (SSR decreases) to 22-79%. SSR change did not regress over 12-day gaps in task performance. A second pair of biceps electrodes, monitored simultaneously, supplied comparable data, indicating that SSR amplitude change occurred throughout the muscle. Beyond 40 ms after pulse onset, elbow extension was inversely correlated with SSR amplitude. The delay between the SSR and its apparent effect on movement is consistent with expected motor-unit contraction time. The data demonstrate that the SSR is capable of adaptive change. At present the most likely site(s) of the mechanism of SSR amplitude change are the Ia synapse and/or the muscle spindle. Available related evidence suggests persistent segmental change may in fact come to mediate SSR amplitude change. If so, such segmental change would constitute a technically accessible fragment of a memory.


Subject(s)
Adaptation, Physiological , Macaca mulatta/physiology , Macaca nemestrina/physiology , Macaca/physiology , Neuronal Plasticity , Reflex, Stretch , Spinal Cord/physiology , Animals , Electromyography , Male , Movement , Muscles/physiology
11.
Brain Res ; 267(1): 196-200, 1983 May 09.
Article in English | MEDLINE | ID: mdl-6860948

ABSTRACT

Monkeys can change the amplitude of the spinal stretch reflex without change in initial alpha motor neuron tone, as measured by EMG, or in initial muscle length. Change is apparent in 5-10 days, continues to develop over weeks, and persists during inactive periods. Spinal stretch reflex change may be a valuable system for studying the neuronal and synaptic bases of an adaptive change in primate CNS function.


Subject(s)
Motor Neurons/physiology , Neuronal Plasticity , Reflex, Stretch , Spinal Cord/physiology , Animals , Electromyography , Macaca mulatta , Macaca nemestrina , Male
12.
J Neurophysiol ; 48(6): 1289-1301, 1982 Dec.
Article in English | MEDLINE | ID: mdl-6130129

ABSTRACT

1. In an effort to identify the neurotransmitter released from terminals of the lateral olfactory tract (LOT) we have studied excitatory amino acid agonist and antagonist actions on population and single-unit responses in submerged and perfused slices of rat prepyriform cortex. Previous studies suggest that the transmitter at this synapse is either aspartate (Asp) or glutamate (Glu). 2. The field potential reflecting the monosynaptic activation of pyramidal neurons after stimulation of the LOT was reversibly depressed by bath perfusion of agonists, with an order of potency being kainic acid (KA) greater than N-methyl-DL-aspartate (NMDA) greater than homocysteic acid (HC) greater than Asp = Glu. 3. The synaptic field potential was essentially unaffected by DL-alpha-aminoadipic acid (AA), 2-amino-3-phosphonopropionic acid (APP), and DL-alpha-diaminopimelic acid (DAPA), all presumed to be selective for Asp receptors, and by L-glutamic acid diethyl ester (GDEE), presumed to be specific for Glu receptors. The field potential was depressed or abolished by 2-amino-4-phosphonobutyric acid (APB), an agent known to block Glu responses in insect muscle. 4. The effects of ionophoretic application of agonists were studied on single neurons recorded extracellularly. While there was some variability among neurons in relative agonist potency, all neurons were excited by the five agonists with relative potencies in general similar to those observed for the field potentials. 5. Responses to Glu and Asp were unaffected by AA, GDEE, and APB at concentrations up to 5 X 10(-3) M. Responses to KA, NMDA, and HC were often depressed by APB but were unaffected by the other antagonists. The excitation on stimulation of the LOT was consistently, rapidly, and reversibly blocked by APB. 6. These observations are not consistent with either Glu or Asp being the neurotransmitter of the LOT.


Subject(s)
Aspartic Acid/physiology , Glutamates/physiology , Neurotransmitter Agents , Olfactory Bulb/physiology , Synaptic Transmission , Animals , Cats , Glutamic Acid , In Vitro Techniques , Iontophoresis , Olfactory Bulb/drug effects , Olfactory Pathways/physiology , Rats , Species Specificity , Synaptic Transmission/drug effects
14.
Cell Mol Neurobiol ; 1(1): 115-20, 1981 Mar.
Article in English | MEDLINE | ID: mdl-6125264

ABSTRACT

Aspartate and glutamate are the principal candidates for the excitatory neurotransmitter released by the lateral olfactory tract (LOT) in prepyriform cortex of the rat. Identity of action of the natural transmitter with exogenous glutamate and/or aspartate, however, has not yet been demonstrated. We show that bath-applied 2-amino-4-phosphonobutyric acid, a presumed specific glutamate antagonist, blocks LOT-stimulated prepyriform field potentials and single unit activity but not the single unit response to ionophoretically applied glutamate or aspartate in rat olfactory cortex slices. These results suggest that neither aspartate nor glutamate is the LOT transmitter. Responses to ionophoretically applied N-methyl-DL-aspartate, kainic acid, and DL-homocysteate were clearly decreased by 2-amino-4-phosphonobutyric acid. This suggests that these agents, usually presumed to be aspartate or glutamate agonists, act at different receptors than aspartate and glutamate.


Subject(s)
Aspartic Acid/pharmacology , Central Nervous System/physiology , Cerebral Cortex/physiology , Glutamates/pharmacology , Neurotransmitter Agents/pharmacology , Olfactory Pathways/physiology , Aminobutyrates/pharmacology , Animals , Cerebral Cortex/drug effects , Glutamic Acid , In Vitro Techniques , Olfactory Pathways/drug effects , Rats
15.
Brain Res ; 194(1): 244-8, 1980 Jul 21.
Article in English | MEDLINE | ID: mdl-6247034

ABSTRACT

The responses to application of TRH were examined on 38 identified neurons in sensory motor cortex of cat. Two pyramidal tract (PT) and 3 nonpyramidal tract (NPT) neurons were directly excited by TRH. Two other NPT neurons were inhibited by TRH. TRH potentiated the excitatory action of ACh on 4 of 12 PT neurons and 1 of 2 unidentified cells. None of these neurons showed a direct effect of TRH. TRH did not potentiate the response to Glu on 12 cells tested, even when the same cell showed TRH modulation of the ACh response. None of the NPT cells examined showed TRH modulation of the excitatory ACh response. These results demonstrate that TRH has multiple actions in mammalian cerebral cortex, but that these actions, such as the modulation of the ACh responses, appear to exist on discrete populations of neurons.


Subject(s)
Somatosensory Cortex/drug effects , Thyrotropin-Releasing Hormone/pharmacology , Acetylcholine/pharmacology , Animals , Cats , Neural Inhibition/drug effects , Neurons/drug effects , Pyramidal Tracts/drug effects , Synaptic Transmission/drug effects
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