The dominant lethal effects of some ergot alkaloids

The dominant lethal test was carried out in the mouse using the ergot derivatives dihydroergotoxine, ergotamine and methysergide. A significant increase in early fetal deaths was induced by 100 mg/kg of dihydroergotoxine and methysergide. Doses of 25 mg/kg and 50 mg/kg did not induce positive effects. Ergotamine was not effective in doses up to 100 mg/kg. Reduced numbers of implantations were not consistently observed following treatment with the ergot preparations, but some anti-fertility effects were noted. Cyclophosphamide, used as a positive control compound, produced significant effects in doses as low as 25 mg/kg.     

Biotechnology of ergot alkaloids

The ergot alkaloids are a group of pharmacologically active compounds produced primarily by species of Claviceps, a fungal parasite of grasses and cereals.

Ergot is of historical interest: medieval midwives collected the fungus from naturally infected plants and used it in the induction of childbirth and in the control of postpartum bleeding. Many additional uses of the ergot alkaloids have been discovered since then, and yet the method of production has persisted to this day basically unchanged.

However, submerged culture of Claviceps is starting to supersede the use of systematically infected rye and a number of new opportunities, including the development of high yielding fungal strains and the production of semi-synthetic alkaloids, have become apparent.     

Effects of ergot alkaloids on stress-induced analgesia

Repeated, thirty minute anticipation of unavoidable painful stimulation causes endorphin-induced analgesia in rats. This type of stress-induced analgesia (SIA) develops rapidly during the first minutes of the exposure to anticipation stress. SIA can be demonstrated during the whole period of anticipation stress. Ergot drugs (DH--ergotoxine, lisuride, trans-9,10 dihydrolisuride) administered 30 min before the onset of anticipation stress, blocked completely this form of SIA. On the other hand, no effect of ergot alkaloids in the tail-flick latency, as measured under resting conditions, was observed. Possible interactions of ergot alkaloids with opiate receptors as an important mechanism by which ergot drugs affect SIA are discussed.     

Biotechnology and genetics of ergot alkaloids

Ergot alkaloids, i.e. ergoline-derived toxic metabolites, are produced by a wide range of fungi, predominantly by members of the grass-parasitizing family of the Clavicipitaceae. Naturally occurring alkaloids like the D-lysergic acid amides, produced by the "ergot fungus" Claviceps purpurea, have been used as medicinal agents for a long time. The pharmacological effects of the various ergot alkaloids and their derivatives are due to the structural similarity of the tetracyclic ring system to neurotransmitters such as noradrenaline, dopamine or serotonin. In addition to "classical" indications, e.g. migraine or blood pressure regulation, there is a wide spectrum of potential new applications of this interesting group of compounds. The biotechnology of ergot alkaloids has a long tradition, and efficient parasitic and submerse production processes have been developed; the biochemistry of the pathway and the physiology of production have been worked out in detail. The recent identification of a cluster of genes involved in ergot alkaloid biosynthesis in C. purpurea and the availability of molecular genetic techniques allow the development of strategies for rational drug design of ergoline-related drugs by enzyme engineering and by biocombinatorial approaches.     

Separation of ergot alkaloids by adsorption on silicates

A mixture of ergot alkaloids (agroclavine, elymoclavine, chanoclavine, and chanoclavine aldehyde) was separated from the Claviceps purpureafermentation broth by adsorption on inorganic adsorbents containing silica. The uptake of alkaloids depended on the concentration of adsorbent and pH. The adsorption capacity for of inorganic materials increased with increasing content of inorganic oxides such as MgO and CaO in the adsorbent. Using statistical thermodynamics, a simple mathematical model describing the multicomponent adsorption equilibrium is proposed and a numerical method suitable for fast computer simulation of multicomponent adsorption was developed.     

The effects of calcium and magnesium ions on the adenosine triphosphatase and inosine triphosphatase activities of myosin A

1. The effects of Ca(2+) and Mg(2+) on the enzymic activity of myosin were studied with myosin preparations treated by the ion-exchange resin Chelex-100. A reaction mixture containing 0.05m-potassium chloride was chosen in which the effects of univalent ions such as K(+), Na(+) and Cl(-) do not change significantly with small variations in their concentrations. 2. The relationship between the rate of hydrolysis of ATP or ITP and the concentration of Ca(2+) suggests that a relatively weak binding of Ca(2+) either to myosin or to the substrate nucleotide is responsible for the activation of the enzymic activity. According to the experiments with an ultrafiltration technique, the binding of Ca(2+) to myosin proceeds in at least two steps, the first occurring at one site on every 500000 atomic mass units of myosin with an apparent association constant, K(app.), 1.3x10(6)m(-1), and the second seeming to be so weak that its binding parameters cannot be determined by the method used. The first type of Ca(2+) binding is not observable with N-ethylmaleimide-modified myosin, yet this modified myosin shows activation by Ca(2+) of its adenosine triphosphatase and inosine triphosphatase. 3. The inhibition by Mg(2+) can be related to a binding reaction of Mg(2+) with myosin having K(app.) approximately 10(6)m(-1). Mg(2+) replaces the Ca(2+) bound tightly to myosin. The K(app.) for Mg(2+)-myosin binding calculated by assuming a competition between Ca(2+) and Mg(2+) for the same site is 2.1x10(5)-3.0x10(5)m(-1). When myosin is modified with a thiol reagent (p-mercuribenzoate) at a certain ratio to myosin, the inhibition by Mg(2+) becomes unobservable. 4. The behaviour of the hydrolytic activity of myosin on ATP or ITP in the presence of both Ca(2+) and Mg(2+) is consistent with the explanation that the inhibition by Mg(2+) is due to the tight binding of Mg(2+) to myosin, whereas the activation by Ca(2+) is caused either by a weak binding of Ca(2+) to myosin or by CaATP(2-) or by both.     

Fructosylation of ergot alkaloids by yeast invertase

Summary A method for transfructosylation of ergot alkaloids elymoclavine, chanoclavine, lysergol, 9, 10-dihydrolysergol using commercial yeast -fructofuranosidase and sucrose is described     

Analysis of ergot alkaloids — a review

Methods for detection and determination of ergot alkaloids in grains, grasses, feeds and grain foods are reviewed. They incorporate simple detection procedures - colorimetry, thin layer chromatography and enzyme-linked immunosorbent assay - or instrumental procedures such as liquid chromatography with fluorescence, mass spectrometric (MS) or MS/MS detection, capillary zone electrophoresis, and direct MS/MS.