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Biomedical subjects

B Meldrum

Publications and source records attributed to B Meldrum.

At least 37 records · Page 2Linked to original sources
PubMed1985

Excitatory aminoacid antagonists provide a therapeutic approach to neurological disorders.

Excessive excitation by neurotransmitters can cause the death of neurons. This excitotoxic action may be responsible for neuronal loss in stroke, cerebral palsy, epilepsy, ageing and Alzheimer's disease, Huntington's disease, and other chronic degenerative disorders. Compounds acting specifically to antagonise excitatory neurotransmission offer a novel therapeutic approach to these disorders.

Adult↗
PubMed1985

2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission--I. Anticonvulsant properties.

2-Amino-6-trifluoromethoxy benzothiazole (PK 26124) prevented convulsions induced in rodents by maximal electroshock, inhibitors of the synthesis of gamma-aminobutyric acid (GABA) and ouabain, but was inactive against seizures provoked by GABA antagonists, unlike diazepam, chlordiazepoxide, phenobarbital and valproic acid. 2-Amino-6-trifluoromethoxy benzothiazole prevented seizures induced by sound stimuli in DBA/2 mice (ED50 = 0.66; 2.1 and 4.1 mg/kg, i.p. according to the seizure component), postural seizures in El mice (ED50 = 7.5 mg, i.p.) and seizures induced by photic stimulation in the baboon, Papio papio, at 4 and 8 mg/kg (i.v.). This spectrum of anticonvulsant activity closely resembles that reported previously for dicarboxylic amino acid antagonists. Indeed, PK 26124 prevented seizures induced by L-glutamate (ED50 = 8.5 mg/kg, i.p.) or by kainate (ED50 = 9.25 mg/kg, i.p.) and tremors induced by harmaline (ED50 = 2.5 mg/kg, i.p.) In these tests diazepam was inactive (L-glutamate) or as potent as PK 26124 (kainate, harmaline), whereas it was 10-20 times more potent than PK 26124 against seizures induced by inhibitors of the synthesis of GABA. Together, these data suggest that PK 26124 possesses antagonistic properties of excitatory dicarboxylic amino acids, which may contribute to its anticonvulsant action.

Amino Acids↗
PubMed1984

Behavioural and convulsant actions of two methyl esters of beta-carboline-3-carboxylic acid in photosensitive baboons and in DBA/2 mice.

The proconvulsant and convulsant actions of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and of methyl-beta-carboline-3-carboxylate (beta-CCM) have been evaluated in two animal models of reflex epilepsy, the photosensitive baboon, Papio papio, and the audiogenic seizure prone DBA/2 mouse. In baboons, myoclonic responses to photic stimulation are markedly enhanced 1 min after DMCM, 0.25 mg/kg i.v. In the absence of photic stimulation DMCM, 0.5 mg/kg i.v. induces a single brief tonic clonic seizure within 10-90 s. beta-CCM, 0.025-0.05 mg/kg i.v. similarly enhances myoclonic responses to photic stimulation. Generalised seizures occur without photic stimulation 0.5-3 min after beta-CCM, 0.1-0.2 mg/kg. Pretreatment with the excitatory amino acid antagonist, 2-amino-7-phosphonoheptanoic acid (2-APH), 110 mg/kg i.v., prevents the generalised seizures induced by DMCM, 0.5 mg/kg, but not those induced by beta-CCM, 0.1-0.2 mg/kg. In DBA/2 mice beta-CCM and DMCM are indistinguishable in potency as convulsants (ED50 values for clonic seizures: 4.4 and 4.6 mg/kg i.p. respectively) and as proconvulsants (ED50 values for facilitation of clonic seizure responses to an 83 dB sound stimulus: 0.25 and 0.23 mg/kg). Pretreatment with 2-APH gives equipotent protection against audiogenic seizures induced by beta-CCM, 1 mg/kg or DMCM, 1 mg/kg. The differences in relative potency of beta-CCM and DMCM in the two species are probably accountable for in terms of differing metabolism. A differential action of the two beta-carbolines on receptor subtypes, with enhancement of excitatory amino acid release playing a more important role in epileptogenesis after DMCM, is proposed.

2-Amino-5-phosphonovalerate↗
PubMed1984

GABAergic agents as anticonvulsants in baboons with photosensitive epilepsy.

GABAergic agents have been evaluated for acute anticonvulsant activity in baboons, Papio papio with photosensitive epilepsy. The potent GABAA agonists muscimol and THIP are proconvulsant. (-)Baclofen, 2 mg/kg suppresses myoclonic responses; higher doses facilitate EEG paroxysmal activity. (S) gamma-vinyl GABA, 100-200 mg/kg, suppresses myoclonic responses for more than 24 h. Some derivatives of esters of beta-carboline-3-carboxylate that bind to the benzodiazepine receptor, e.g. ZK 91296 and ZK 93423, suppress myoclonus with a potency at least as great as diazepam.

Aminocaproates↗
PubMed1984

Amino acid neurotransmitters and new approaches to anticonvulsant drug action.

Amino acids provide the most universal and important inhibitory (gamma-aminobutyric acid (GABA), glycine) and excitatory (glutamate, aspartate, cysteic acid, cysteine sulphinic acid) neurotransmitters in the brain. An anticonvulsant action may be produced (1) by enhancing inhibitory (GABAergic) processes, and (2) by diminishing excitatory transmission. Possible pharmacological mechanisms for enhancing GABA-mediated inhibition include (1) GABA agonist action, (2) GABA prodrugs, (3) drugs facilitating GABA release from terminals, (4) inhibition of GABA-transaminase, (5) allosteric enhancement of the efficacy of GABA at the receptor complex, (6) direction action on the chloride ionophore, and (7) inhibition of GABA reuptake. Examples of these approaches include the use of irreversible GABA-transaminase inhibitors, such as gamma-vinyl GABA, and the development of anticonvulsant beta-carbolines that interact with the "benzodiazepine receptor." Pharmacological mechanisms for diminishing excitatory transmission include (1) enzyme inhibitors that decrease the maximal rate of synthesis of glutamate or aspartate, (2) drugs that decrease the synaptic release of glutamate or aspartate, and (3) drugs that block the post-synaptic action of excitatory amino acids. Compounds that selectively antagonise excitation due to dicarboxylic amino acids have recently been developed. Those that selectively block excitation produced by N-methyl-D-aspartate (and aspartate) have proved to be potent anticonvulsants in many animal models of epilepsy. This provides a novel approach to the design of anticonvulsant drugs.

4-Aminobutyrate Transaminase↗
PubMed1982

Protection against chemically induced seizures by 2-amino-7-phosphonoheptanoic acid.

The anticonvulsant activity of 2-amino-7-phosphonoheptanoic acid (2APH) (an antagonist of excitation induced by N-methyl-D-aspartic acid) was studied against N-methyl-DL-aspartic acid (NMDLA), kainic acid, 3-mercaptopropionic acid (3MPA), thiosemicarbazide (TSC), quinolinic acid, bicuculline, picrotoxin and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in Swiss S mice. 2APH, 0.33 mM/kg i.p., antagonizes convulsions induced by NMDLA, 3MPA, TSC, DMCM and picrotoxin but not those produced by the other convulsants. It is proposed that an aspartergic component may contribute to the development of convulsions after 3MPA, TSC, DMCM and picrotoxin.

2-Amino-5-phosphonovalerate↗
PubMed1982

Production and reproduction. Women and breastfeeding: some Nigerian examples.

Breastfeeding is of crucial importance in the developing world, not only to the health of the mother and her infant, but to the community in general. The importance of breastfeeding of infants lies not only in its nutritional and hygienic properties, but also because of its immunological effects and its influence in the control of fertility. The literature review is combined with a discussion of aspects of research undertaken by the authors under the headings of length of breastfeeding, bottlefeeding and breastfeeding and fertility. Most of the examples come from Nigeria, but the problems discussed are common to much of the developing world. Under a discussion of social and policy implications, the need for governments in the developing countries to adopt the recent World Health Organisation's code of practice to curtail the sale of artificial infant milks, is stressed. It is suggested that health agencies in countries like Nigeria should go to the rural areas now, to instruct the women and men in the dangers of bottle feeding and the benefits of breastfeeding, before the 'modernisation' of infant feeding, so evident in the towns, spreads to the rural areas.

Birth Intervals↗
PubMed1982

Pharmacology of GABA.

GABA-ergic systems are involved in all the main functions of the brain. In most brain regions impairment of this system produces epileptic activity. GABA-mediated inhibitory function can be enhanced by drugs of at least seven different types. They act on the metabolism or synaptic release of GABA, or its reuptake into neurones of glia, or on various components of the GABA receptor complex (GABA recognition site, "benzodiazepine" receptor or chloride ionophore). Among such compounds, those which act most specifically and potently on GABA receptors remain primarily research tools. Among compounds in clinical use, valproate, benzodiazepines, and anticonvulsant barbiturates al enhance GABA-mediated inhibition. In the future, new inhibitors of GABA uptake, new GABA agonists and potent inhibitors of GABA-transaminase are likely to become available. Trials of drugs enhancing GABA-ergic function have been made in a wide variety of neurological disorders. In most forms of epilepsy a therapeutic effect is evident. Real benefit from GABA therapies has not been demonstrated in the principal disorders of movement (Huntington's chorea, Parkinson's disease, dystonias), except in so far as they have a myoclonic or paroxysmal component. Among psychiatric disorders the acute symptoms of schizophrenia are exacerbated by enhanced GABA-ergic function. Abstinence syndromes (alcohol, barbiturate or narcotic withdrawal) are ameliorated by drugs enhancing GABA-ergic function, and there is some evidence for a beneficial action in anxiety states and mania. Attempts to relate the molecular neurobiology of GABA with clinical pharmacology are of very recent origin. Improved understanding of the variety of GABA receptor mechanisms will provide the key to the more selective pharmacological manipulations that are required for therapeutic success.

4-Aminobutyrate Transaminase↗
PubMed1981

Cerebral and extracerebral blood volume in generalized seizures in the baboon Papio papio.

Relative variations of the cerebral and extracerebral blood volume (CBV) were measured continuously by a novel atraumatic method in baboons to explore the relationship between changes in the systemic circulation and in the cerebral (and extracerebral) vascular responses, before, during and after generalized seizures induced by photic stimulation. Major bursts of generalized spikes and waves are accompanied by an increase of the mean arterial pressure and of the cerebral blood volume and a decrease of the nasal blood volume. During the seizure discharge a substantial increase in CBV occurs, associated with a dramatic increase in arterial pressure. However, the greatest increase in CBV occurs after the peak mean arterial pressure. The results show that the CBV does not passively follow the blood pressure and demonstrate the dramatic responsiveness of the nasal region to seizure discharge.

Animals↗
PubMed1981

Aporphines. 34. (-)-2,10,11-Trihydroxy-N-n-propylnoraporphine, a novel dopaminergic aporphine alkaloid with anticonvulsant activity.

(-)-2,10,11-Trihydroxy-N-n-propylnoraporphine (TNPA,2c) has been synthesized from thebaine (3a), via northebaine (3b), normorphothebaine (2a), and alkylation to the N-propyl derivative 2b. O-Demethylation gave the desired product 2c. Compound 2c showed activity comparable to its 10,11-dihyroxy counterpart (NPA, 1b) on the stimulation of dopamine-sensitive adenylate cyclase in carp retinal homogenates. The evaluation of 2c on audiogenic seizures in mice, in the protection against paroxysimal EEG and myoclonic response to photic stimulation in the baboon, revealed a similar pharmacological profile in comparison to NPA and apomorphine, with TNPA showing a prolonged duration of action in abolishing myoclonic response to photic stimulation in the baboon.

Acoustic Stimulation↗