Extracts and constituents of Hypericum perforatum inhibit the binding of various ligands to recombinant receptors expressed with the Semliki Forest virus system.

Extracts, fractions and constituents of Hypericum perforatum were studied for in vitro receptor binding with various ligands to recombinant CNS receptors expressed with the Semliki Forest virus expression system. For this purpose we have prepared membranes of CHO cells with high density of several opioid, serotonin, estrogen, histamine, GABAA, neurokinin and metabotropic glutamate receptors, respectively. A lipophilic Hypericum fraction revealed relatively potent inhibition to the binding of the mu-, delta- and kappa-opioid and the 5-HT6 and 5-HT7 receptors.

Hypericum perforatum inhibits the binding of mu- and kappa-opioid receptor expressed with the Semliki Forest virus system.

The effects of Hypericum perforatum extracts on in vitro [3H]naloxone binding to the human mu- and rat kappa-opioid receptors were studied in chinese hamster ovary (CHO) cells using the Semliki Forest virus (SFV) expression system. Binding of [3H]naloxone to the mu- and kappa-opioid receptor was inhibited in the presence of Hypericum extracts showing IC50 values of approximately 25 and 90 micrograms/ml, respectively. In contrast, extracts of Valeriana officinalis did not inhibit binding to the mu-opioid receptor.

Inhibition of benzodiazepine binding in vitro by amentoflavone, a constituent of various species of Hypericum.

Flower extracts of Hypericum perforatum, Hypericum hirsutum, Hypericum patulum and Hypericum olympicum efficiently inhibited binding of [3H]flumazenil to rat brain benzodiazepine binding sites of the GABAA-receptor in vitro with IC50 values of 6.83, 6.97, 13.

[The combined use of photodynamic therapy with ionizing radiation on breast carcinoma cells in vitro].

Purpose: The photodynamic therapy is a technique by which the tumor cells are selectively sensitized to destruction by light of an appropriate wavelength. The aim of this work is to analyze the biological effectiveness of photochemical reactions induced by laser light in tumor cells exposed to photosensitizers.

Material And Methods: The toxicity of the 2 photosensitizers zinc phthalocyanine (ZnPC) and meso-tetrahydroxyphenylchlorine (m-THPC) as well as the biological effect of the combination of sensitizers with laser light were tested in vitro by means of a colony forming assay.

Pharmacology of moclobemide.

Moclobemide is a reversible inhibitor of monoamine oxidase (MAO) with clear preference for the A type (so-called RIMA). The enzyme inhibition shows complex kinetics, and the molecular mechanism of interaction with the enzyme is not yet clear. Moclobemide increases the extracellular concentration of the monoamines in rat brain and decreases the level of their metabolites.

Biochemistry and pharmacology of moclobemide, a prototype RIMA.

RIMA is a term for reversible inhibitors of monoamine oxidase (MAO) with preference for MAO-A; moclobemide is a prototype of this new class of antidepressants and is a highly selective inhibitor of MAO-A in vitro. This inhibition is reversible by dialysis in vitro, which accounts for the dose-dependent duration of in vivo enzyme inhibition of 12-24 h. Moclobemide increases the content of serotonin, noradrenaline and dopamine in the brain, and decreases that of their deaminated metabolites.

Interaction of moclobemide and tricyclic antidepressants with the tyramine pressor effect in rats.

Tyramine at high doses (20 mg/kg) increased arterial blood pressure in freely moving rats. This increase was completely prevented by pretreatment with inhibitors of neuronal membrane carriers for noradrenaline (e.g.

Some basic aspects of reversible inhibitors of monoamine oxidase-A.

A novel class of antidepressants is emerging with considerable therapeutic potential: reversible inhibitors of monoamine oxidase type A (RIMA). Moclobemide (Aurorix) is a representative RIMA. It is a fully and rapidly reversible inhibitor of MAO-A with a correspondingly intermediate duration of action in vivo.

Hypotensive action and weak potentiation of tyramine effect by moclobemide in rats.

Moclobemide belongs to a new class of reversible, selective monoamine oxidase-A (MAO-A) inhibitors; it is clinically well tolerated and has little liability to potentiate tyramine pressor effects. Measurement of blood pressure and heart rate in conscious, freely moving rats showed only a slight, nonsignificant decrease in mean arterial pressure in normotensive animals. However, in spontaneously hypertensive rats, moclobemide significantly decreased blood pressure by 20 mmHg within 30 min of oral intake of 30 mg/kg.

Short-lasting and reversible inhibition of monoamine oxidase-A by moclobemide.

In ex vivo experiments, the time course of monoamine oxidase-A (MAO-A) inhibition after 10 mg/kg oral moclobemide was virtually the same for whole rat brains and liver: the onset was rapid, the maximum effect was obtained in 15 min, and the duration of action was short (about 16 h) compared with several days for the irreversible MAO inhibitors. The time course of MAO-B inhibition was peculiar: almost complete inhibition was obtained in the time only between the first and second hours, whereas in the whole brain, or various brain areas, maximum MAO-B inhibition (40%) did not occur until 2 h after drug administration. Inhibition in other peripheral organs, such as kidney and small intestine, was of even shorter duration (3 h).

Comparison of monoamine oxidase-A inhibition by moclobemide in vitro and ex vivo in rats.

Inhibition of MAO activity was measured in rat brain homogenates using 5-HT as MAO-A substrate and phenylethylamine as MAO-B substrate. Moclobemide rather selectively inhibited MAO-A. Its inhibitory potency is rather low, like that of toloxatone, whereas clorgyline, harmaline, cimoxatone and brofaromine were all found to be at least 100 times more potent.

An opioid agonist with preference for kappa-opioid receptors: (-)-N-cyclopropylmethylmorphinan-6-one.

N-Cyclopropylmethyl- and N-cyclobutylmethylmorphinan-6-one (3 and 4, respectively) were prepared from N-methylmorphinan-6-one. The pharmacological studies showed 3 and 4 to be potent opioid agonists. Compound 3 was found to have preference for kappa rather than mu opioid receptors.

Pre-clinical pharmacology of moclobemide. A review of published studies.

The novel antidepressant, moclobemide, is a reversible inhibitor of monoamine oxidase (MAO) preferentially of monoamine oxidise-A (MAO-A); it emerged for study out of a series of lipid-lowering agents. In spite of its weak MAO-A inhibition in vitro, moclobemide is a potent inhibitor of MAO-A, in vivo; its in vivo activity is of short duration, in contrast to the extremely long-lasting inhibition, e.g.

[Hyperthermia--a new element in cancer treatment].

The efficacy of radiation therapy combined with local hyperthermia is demonstrated by three case studies. Mode of action and problems are discussed and published results reported. Human tumour cells obtained of biopsies from our patients before the onset of treatments were investigated.

Synthesis and biological evaluation of 14-alkoxymorphinans. 2. (-)-N-(cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one, a selective mu opioid receptor antagonist.

(-)-N-(Cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one (2) was synthesized with 4,14-dimethoxy-N-methylmorphinan-6-one (1) as starting material. In vivo and in vitro experiments show 2 (cyprodime) to be a pure opioid receptor antagonist. Some of these tests (opioid receptor binding assays, guinea pig ileal longitudinal muscle preparation, rat and mouse vas deferens preparation, acetic acid writhing antagonism test) indicate that 2 is a selective mu opioid receptor antagonist.

Pharmacological profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A.

The novel antidepressant moclobemide is a reversible inhibitor of monoamine oxidase (MAO), preferentially of type A. Moclomide was active in three animal models considered predictive for antidepressant activity: 1) it prevented dose-dependently akinesia and blepharospasm induced in mice and rats by Ro 4-1284, a short-acting amine releasing agent. Prevention of akinesia by moclobemide also depended upon the dose of Ro 4-1284.

Neurochemical profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A.

Moclobemide belongs to a new generation of short-acting, reversible, monoamine oxidase (MAO) inhibitors. In vitro (rat brain homogenates) moclobemide inhibits MAO-A selectively with lower potency than many of the reference MAO inhibitors. However, when measured ex vivo in the rat, the potency of moclobemide is similar to that of reference compounds.

Preclinical profiles of the novel reversible MAO-A inhibitors, moclobemide and brofaromine, in comparison with irreversible MAO inhibitors.

Acceptance into clinical practice of monoamine oxidase (MAO) antidepressants requires unequivocal evidence that novel, non-hepatotoxic and reversible MAO-A inhibitors carry little or no risk of inducing severe hypertensive crises (cheese effect). This study summarizes the most relevant preclinical aspects which differentiate the novel reversible MAO-A inhibitors moclobemide and brofaromine, from previous irreversible MAO inhibitors of the old generation, particularly phenelzine and tranylcypromine. Moclobemide and brofaromine bear no chemical relation to irreversible inhibitors such as hydrazine derivatives (phenelzine) or aminocyclopropyl derivatives (tranylcypromine).

Ro 15-4513: partial inverse agonism at the BZR and interaction with ethanol.

The imidazobenzodiazepinone derivative Ro 15-4513 has the activity profile of a partial inverse (low efficacy) agonist at the benzodiazepine receptor (BZR). It reverses central nervous depressant effects of diazepam, and, in part, of phenobarbitone and ethanol in mice, rats and cats in behavioural, electrophysiological, and neurochemical paradigms. The interaction of Ro 15-4513 with barbiturates and ethanol is due to its inverse agonistic (negative allosteric modulatory) property at the BZR, as it was reversed by the selective BZR blocker flumazenil (Ro 15-1788).