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P Martin

Publications and source records attributed to P Martin.

At least 739 records · Page 41Linked to original sources
PubMed1988

Antidepressant-like effects of triiodothyroacetic acid in mice.

Triiodothyroacetic acid (TA3) is a natural thyroid analogue which possesses some of the properties of triiodothyronine (T3). In particular, it has an inhibitory effect on the thyreotropic axis, but its peripheral effects are reduced. Given the activity of T3 on psychopharmacological models of depression in rodents, we investigated the effects of TA3 on some pharmacological and behavioral tests in mice. TA3 antagonized apomorphine- and oxotremorine-induced hypothermia, potentiated yohimbine-induced toxicity and L-5-hydroxy-tryptophan-induced head twitches, but did not affect forced swimming-induced immobility or reserpine-induced hypothermia. Thus, TA3 was effective on the same psychopharmacological tests which have previously been used to demonstrate the antidepressant-like effects of T3. Moreover, TA3 under the same experimental conditions as T3 has little effect on the metabolic clearance rate parameters, and might, therefore, be preferable to T3 for clinical use in depression.

Animals↗
PubMed1988

Gamma-vinyl GABA: comparison of neurochemical and anticonvulsant effects in mice.

Biochemical and pharmacological effects of gamma-vinyl GABA (Vigabatrin, GVG), and irreversible enzyme-activated inhibitor of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T), were measured in mice. This anticonvulsant produced a time- and dose-dependent elevation of the GABA, phenylalanine and lysine contents of cortical tissue and simultaneously decreased glutamate, aspartate and alanine levels. In addition, GVG caused a biphasic change in glutamine concentrations (a decline 1-4 hours after administration, followed 20 hours later by an increase). Moreover, we found a new, as yet unidentified amino acid in the brain eluting with the same retention time as alpha-aminoadipic acid from an HPLC cation-exchange column. The level of this novel chemical entity was greatly increased by GVG 20 hours after injection of the drug. At all tested intervals between 1 and 60 hours after injection, GVG was ineffective against maximal electroshock. The GABA-T inhibitor dose-dependently protected mice against isoniazid-induced seizures, simultaneously causing an increase in brain GABA concentrations. However, this apparent correlation applied only until 4 hours after treatment. To better define the anticonvulsant profile of GVG, groups of mice were treated, 1, 2, 4, and 24 hours prior to challenge with convulsant doses of strychnine, pentetrazole (PTZ), and picrotoxin, and brain amino acid levels, including brain concentrations of GVG, were measured. In all instances, the time dependency of the anticonvulsant effects of GVG and of increases in brain GABA levels differed. Amino acid concentrations in animals treated only with GVG were similar to those in animals given GVG and a chemical convulsant. GVG showed no selectivity for seizures produced by impairment of GABA-ergic neurotransmission. Although GVG is an effective GABA-T inhibitor, it apparently affects several other pyridoxal-phosphate-dependent cerebral enzymes and/or interacts with other neurotransmitter systems as well.

4-Aminobutyrate Transaminase↗
PubMed1988

Evaluation of the anticonvulsant and biochemical activity of CGS 8216 and CGS 9896 in animal models.

CGS 8216, a benzodiazepine-receptor ligand with inverse agonistic properties, and CGS 9896, which possesses partial agonistic or mixed agonist-antagonist properties were compared in a number of epilepsy models. The effect of CGS 9896 on the decrease in GABA levels induced by isoniazid was also investigated. CGS 9896 inhibited the kindling process in rats in that it delayed the development of overt seizures and the increase in the duration of afterdischarges. In a genetic rat model characterized by absence-like EEG patterns, CGS 9896 dose-dependently suppressed these spontaneously occurring discharges, while CGS 8216 had no effect. However, CGS 8216 antagonized the anticonvulsant action of CGS 9896. CGS 9896 protected mice against seizures induced by beta-vinyllactic acid, whereas CGS 8216 shortened the latency period before convulsions occurred. CGS 9896 retarded the onset of convulsive fits caused by isoniazid without preventing the decrease in GABA levels produced by that drug. These results confirm the anticonvulsant activity of CGS 9896 and demonstrate the inverse agonistic activity of CGS 8216. The profile of CGS 9896 in the above tests suggests that it might be an effective anticonvulsant, primarily in absence-type seizures.

Animals↗
PubMed1988

The somatostatin/histaminic pathway balance on gastric secretion could be based on a competitive antagonism.

Measurements of acid and pepsin secretions and of histamine release in response to food alone or in combination with graded doses of antramine (AH), a molecular form of histamine isolated from antral mucosa, with or without somatostatin were performed simultaneously in dogs equipped with a denervated pouch. AH restored somatostatin-inhibited acid and pepsin secretions but with different intensities in regard to the different inhibitory levels induced by somatostatin. AH competitively antagonized somatostatin (1 microgram/kg/h) inhibition of acid secretion, but when stronger levels of inhibition were achieved, AH restored weakly acid secretion. Recovery of pepsin secretion occurred through a competitive mechanism between AH and somatostatin (1 and 2 micrograms/kg/h). There was a close relationship between the secretory outputs and the integrated histamine responses; the slopes of the regression lines might be considered as reflecting the stimulatory activity of blood histamine on secreting cells. For acid secretion, this activity is similar in control and somatostatin (1 microgram/kg/h) tests, while for pepsin secretion it is identical in control and 1 or 2 micrograms/kg/h somatostatin tests. One can speculate that the suppression of the somatostatin inhibitory effects by antramine, within the limits of physiological conditions, results from a competitive mechanism.

Amino Acids↗
PubMed1988

Impaired response of experimental diabetic mice to tricyclics: a possible beta-adrenergic mechanism.

Diabetes is reportedly associated with alterations in peripheral and central noradrenergic systems. The latter might be involved in the antidepressant effects of imipramine-like drugs in both humans and animals. Therefore, it is possible that diabetics show an impaired responsiveness to tricyclics. To test this possibility the effects of streptozotocin (STZ)-induced experimental diabetes in mice were assessed in two psychopharmacological tests: 1) the reversal of apomorphine- (16 mg/kg) induced hypothermia and 2) the hypoactivity induced by a direct beta-agonist (clenbuterol 0.06 mg/kg). At day 15 after STZ or vehicle treatment, imipramine (4 mg/kg) antagonized the apomorphine-induced hypothermia in diabetic (D) and nondiabetic (ND) mice and clenbuterol produced hypoactivity in both groups. At day 30 and 45, the ability of imipramine (1, 2, 4, 8, 16 mg/kg), clomipramine (8 mg/kg) and desipramine (2 mg/kg) to reverse apomorphine-induced hypothermia disappeared at the same time that clenbuterol lost its ability to induce hypomotility in D mice. These impaired responses on both tests were corrected by a short period of insulin therapy. These two tests may reflect central beta-adrenergic functions. Therefore, these data suggest that the impaired responsiveness of diabetic mice might be due at least in part to a noradrenergic dysfunction. Possibly, in diabetes, a beta-adrenoceptor desensitization identical to that observed at the peripheral level occurs in the central nervous system. The possibility that a thyroid hormone deficiency may be involved was also tested. Decreased T3 plasma levels were found in D mice concomitant with the impaired pharmacological responses and T3 supplementation turned these responses to normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Selective defect in the antibody response to Haemophilus influenzae type b in children with recurrent infections and normal serum IgG subclass levels.

We studied 15 children with recurrent infections and normal serum IgG, IgM, IgA, and IgG-subclass levels. After immunization, the geometric mean serum IgG antibody concentration to Haemophilus influenzae type b (Hib) was eightfold lower than that of age-matched control subjects (p = 0.002). The patients also had a lower geometric mean concentration of serum IgM and IgA directed to Hib, although these differences did not reach significance. However, the groups did not differ in their response to diphtheria toxoid and pneumococcal polysaccharides. To confirm these findings, an additional 11 patients were identified and immunized. The geometric mean serum IgG anti-Hib concentration for this group of patients was also significantly lower than of normal subjects (p = 0.004). We propose that the defect in the antibody response to Hib may be a marker for a poor antibody response to a variety of bacterial and viral antigens that results in an increased propensity to recurrent infections. The defect was not associated with IgG-subclass deficiency. The identification of children with selective antibody deficiency and recurrent infections is important for diagnostic and therapeutic reasons.

Adolescent↗
PubMed1988

Optimal pharmacokinetic delivery of infused drugs: application to the treatment of cardiac arrhythmias.

A common clinical goal of infusing drugs is to attain therapeutic steady-state concentrations as rapidly as possible. The desire is to closely approximate a step function in plasma concentration of the therapeutic agent. We have developed a novel approach to achieve this goal by using the principles of systems and compartmental analyses. The approach is to build a pharmacokinetic model for the disposition of the drug and then calculate backwards from the desired output function to derive the optimal input infusion function. We applied this technique to the infusion of Lidocaine, an antiarrhythmic agent which is often difficult to control. An optimal infusion function, used to drive a servo-controlled infusion pump, was derived to closely approximate a step-function response of drug levels. The efficacy of this infusion function was verified experimentally in dogs.

Animals↗
PubMed1988

L-leucyl-L-leucine methyl ester treatment of canine marrow and peripheral blood cells. Inhibition of proliferative responses with maintenance of the capacity for autologous marrow engraftment.

Incubation of canine marrow and peripheral blood mononuclear cells with L-leucyl-L-leucine methyl ester resulted in the inhibition of mitogen- and alloantigen-induced blastogenesis, the elimination of allosensitized CTL and NK activity, and prevented the development of CTL from pCTL. The effects of these incubations were similar to those described in mice and humans. Additionally, in vitro CFU-GM growth from treated canine marrow was reduced, but could be regained when the Leu-Leu-OMe-treated marrow was cocultured with either untreated autologous peripheral blood mononuclear cells or monocyte-enriched PBMC but not with untreated monocyte-depleted PBMC. Six of seven dogs conditioned with 920 cGy total-body irradiation engrafted successfully after receiving autologous marrow that was incubated with Leu-Leu-OMe prior to infusion. These cumulative results indicate that incubation with Leu-Leu-OMe is a feasible method to deplete canine marrows of alloreactive and cytotoxic T cells prior to transplantation.

Animals↗
PubMed1988

Nucleotide sequence of Acinetobacter baumannii aphA-6 gene: evolutionary and functional implications of sequence homologies with nucleotide-binding proteins, kinases and other aminoglycoside-modifying enzymes.

A new kanamycin-resistance gene, detected in Acinetobacter baumannii and designated aphA-6, was sequenced. It specifies a 30319 Dalton 3'-aminoglycoside phosphotransferase (APH(3'] that mediates resistance to kanamycin and structurally related aminoglycosides, including amikacin. Pairwise comparisons of the six types of APH(3') so far detected in human pathogens (types I, II, III and VI) and in amino-glycoside-producing microorganisms (types IV and V), confirm that APH(3') enzymes have diverged from a common ancestor. Three highly retained motifs (1: V--HGD----N; 2: G--D-GR/K-G and 3: D--K/R--Y/F---LDE) located in the C-terminal part of the enzymes were defined. Screening of protein sequence data bases fore each of these motifs revealed that motifs 1 and 2 are both found in nucleotide-binding phosphotransferases associated with a variety of biological processes, namely adenylate kinase, viral oncogenic protein kinases, elongation factors, Na+/K+-transporting ATPase, myosin and antibiotic-modifying enzymes. Motif 2 probably corresponds to the MgATP binding site, while motifs 3 and 1 could be involved in the splitting of the phosphodiester bond and in the phosphate transfer, respectively. Moreover, an additional motif, almost invariably centrally located, was found in all aminoglycoside-modifying enzymes. The occurrence of this motif, possibly a recombination site which would have allowed the association of units of separate functions, is compatible with a modular concept for the structure of aminoglycoside-modifying enzymes.

Acinetobacter↗
PubMed1988

Decreased central GABA B receptor binding sites in diabetic rats.

Little is known about the implication of central GABAergic neurons. However, there is evidence suggesting a growing importance of GABAergic function in the action of antidepressants. Since streptozotocin (STZ)-diabetic rats have been shown to be resistant to the action of various antidepressants, we were interested in evaluating the density of GABAergic receptor binding sites in the cortex of STZ-diabetic rats on day 15 and day 30 of diabetes. A specific and marked decrease in GABA B receptor density was observed with no change in GABA A. Although no clear relationship could be demonstrated, it may be suggested that a central GABAergic dysfunction of diabetic rats may contribute to explain their resistance to antidepressants.

Animals↗
PubMed1988

General practice patients on long-term psychotropic drugs. A controlled investigation.

In a health centre, 3.6% of the registered patients were found to have received at least one prescription for psychotropic drugs in each quarter of a year. These patients were mainly elderly and female. Psychiatric interviews were held with randomly selected index patients, and with matched controls. Most index patients reported taking psychotropic drugs for several years, mainly anxiolytics, antidepressants and non-barbiturate hypnotics, and mainly in low dosage. Index patients had much higher levels of psychiatric morbidity, as shown by the Present State Examination, history of specialist psychiatric treatment, and previous drug overdoses. In index patients the main diagnoses were neurotic depression and phobic disorder. Index patients reported more problems with finances and with social isolation.

Adult↗
PubMed1988

Treatment of alcoholic organic brain syndrome with the serotonin reuptake inhibitor fluvoxamine: a preliminary study.

The chronic effects of fluvoxamine (200 mg per day for 4 weeks) were studied in ten alcoholic organic brain syndrome patients in a double-blind cross-over design. Complete neuropsychological evaluation was performed as well as measurement of neurochemical changes in CSF. Fluvoxamine produced a small but significant improvement in memory performance. An analysis of fluvoxamine minus placebo difference scores showed a significant correlation between memory functioning and CSF 5HIAA levels. Alcohol amnestic syndrome patients who had the highest blood levels of fluvoxamine demonstrated the largest changes in CSF 5HIAA and improvement in memory performance under fluvoxamine. These findings implicate a role of serotonergic mechanisms in alcoholic organic brain syndrome and suggest that with individual titration of the drug dose, fluvoxamine might be a clinically useful agent in the treatment of this syndrome.

Aged↗
PubMed1988

Alterations of central serotonin and dopamine turnover in rats treated with ipsapirone and other 5-hydroxytryptamine1A agonists with potential anxiolytic properties.

Measurements of tissue levels of monoamines and their metabolites, and of the rates of 5-hydroxytryptophan and dihydroxy-phenylalanine accumulation after blockade of aromatic amino acid decarboxylase by benserazid indicated that ipsapirone (1-10 mg/kg i.p.) decreased 5-hydroxytryptamine (5-HT) turnover and accelerated dopamine (DA) turnover in various brain regions. The reduced 5-HT turnover probably resulted from the stimulation of 5-HT1A autoreceptors within the anterior raphe nuclei as in vitro tests [( 3H]-8-hydroxy-2-[di-n-propylamino]tetralin binding and adenylate cyclase assays) demonstrated that ipsapirone was a 5-HT1A agonist almost as potent as 8-OH-DPAT, and the same decrease in 5-hydroxytryptophan accumulation could be induced by the i.p. (5 mg/kg) or intraraphe (1 microgram) injection of ipsapirone. Ipsapirone-induced acceleration of DA turnover persisted after the selective degeneration of serotoninergic neurons by intraraphe 5,7-dihydroxytryptamine infusion, and could be reproduced by i.p. administration of other 5-HT1A agonists like buspirone and gepirone, but not 8-OH-DPAT. These results demonstrate that ipsapirone-induced acceleration of DA turnover did not result from the stimulation of 5-HT1A (auto)receptors, but involved additional target(s) of the drug. The possible participation of dopaminergic systems in the "anxiolytic" properties of ipsapirone should deserve further investigations.

Animals↗