Biomedical subjects
E M Williamson
Publications and source records attributed to E M Williamson.
Synergy and other interactions in phytomedicines.
Synergistic interactions are of vital importance in phytomedicines, to explain difficulties in always isolating a single active ingredient, and explain the efficacy of apparently low doses of active constituents in a herbal product. This concept, that a whole or partially purified extract of a plant offers advantages over a single isolated ingredient, also underpins the philosophy of herbal medicine. Evidence to support the occurrence of synergy in within phytomedicines is now accumulating and is reviewed here. Synergistic interactions are documented for constituents within a total extract of a single herb, as well as between different herbs in a formulation. Positive and negative aspects of interactions are discussed together with the methods used to identify and measure synergy. The evidence is divided into experimental, in vitro instances, as well as clinical examples where available. Herbs discussed include Ginkgo biloba, Piper methysticum (Kava-Kava), Glycyrrhiza glabra, Hypericum perforatum, Valeriana officinalis, Cannabis sativa, Salix alba and others.
Cannabinoids in clinical practice.
Cannabis has a potential for clinical use often obscured by unreliable and purely anecdotal reports. The most important natural cannabinoid is the psychoactive tetrahydrocannabinol (delta9-THC); others include cannabidiol (CBD) and cannabigerol (CBG). Not all the observed effects can be ascribed to THC, and the other constituents may also modulate its action; for example CBD reduces anxiety induced by THC. A standardised extract of the herb may be therefore be more beneficial in practice and clinical trial protocols have been drawn up to assess this. The mechanism of action is still not fully understood, although cannabinoid receptors have been cloned and natural ligands identified. Cannabis is frequently used by patients with multiple sclerosis (MS) for muscle spasm and pain, and in an experimental model of MS low doses of cannabinoids alleviated tremor. Most of the controlled studies have been carried out with THC rather than cannabis herb and so do not mimic the usual clincal situation. Small clinical studies have confirmed the usefulness of THC as an analgesic; CBD and CBG also have analgesic and antiinflammatory effects, indicating that there is scope for developing drugs which do not have the psychoactive properties of THC. Patients taking the synthetic derivative nabilone for neurogenic pain actually preferred cannabis herb and reported that it relieved not only pain but the associated depression and anxiety. Cannabinoids are effective in chemotherapy-induced emesis and nabilone has been licensed for this use for several years. Currently, the synthetic cannabinoid HU211 is undergoing trials as a protective agent after brain trauma. Anecdotal reports of cannabis use include case studies in migraine and Tourette's syndrome, and as a treatment for asthma and glaucoma. Apart from the smoking aspect, the safety profile of cannabis is fairly good. However, adverse reactions include panic or anxiety attacks, which are worse in the elderly and in women, and less likely in children. Although psychosis has been cited as a consequence of cannabis use, an examination of psychiatric hospital admissions found no evidence of this, however, it may exacerbate existing symptoms. The relatively slow elimination from the body of the cannabinoids has safety implications for cognitive tasks, especially driving and operating machinery; although driving impairment with cannabis is only moderate, there is a significant interaction with alcohol. Natural materials are highly variable and multiple components need to be standardised to ensure reproducible effects. Pure natural and synthetic compounds do not have these disadvantages but may not have the overall therapeutic effect of the herb.
Suppression of pendular nystagmus by smoking cannabis in a patient with multiple sclerosis.
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Secretion and properties of a polypeptide factor generated by phorbol ester stimulation of human blood platelets.
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The potentiation of phorbol ester-induced aggregation of human platelets by the prostaglandin endoperoxide analogue, U46619.
It was not possible to desensitize human blood platelets to 12-deoxyphorbol-phenylacetate (DOPP) stimulation in a manner analogous with that to platelet aggregating factor (PAF), prostaglandin-endoperoxide analogue (U46619) or adenosine diphosphate (ADP). Platelets previously desensitized to U46619, when challenged with DOPP and ADP, showed an increased aggregation and release of 5-HT. Sub-threshold aggregating doses of U46619 also caused a potentiation of the platelet response and release reaction to DOPP. The concentration of U46619 used to pretreat platelets affected the extent of potentiation of platelet stimulation induced by DOPP. The degree of potentiation was also affected by the time interval between addition of U46619 and DOPP. U46619 did not potentiate the aggregating effects of PAF, or ionophore A23187. The stimulus potentiation of DOPP by U46619 was abolished by prostacyclin (PGI2) and an antibody to U46619, but was unaffected by indomethacin and CP/CPK.
New phorbol and deoxyphorbol esters: isolation and relative potencies in inducing platelet aggregation and erythema of skin.
Diester diterpenes based upon phorbol, 4-deoxyphorbol, 4 alpha-deoxyphorbol, 4-deoxy-5-hydroxyphorbol and 4,20-dideoxy-5-hydroxyphorbol were isolated from the fruit oil of Sapium indicum. Corresponding tri- and tetra-esters were produced by acetylation and mono-esters by selective hydrolysis. Twenty-six compounds were tested for production of erythema in vivo and induction of human and rabbit platelet aggregation in vitro. The flatter shape of the AB-ring trans compounds is necessary for interaction of phorbolesters at their receptor in that the cis analogues were inactive. The tertiary C-4 hydroxy group of phorbol was not necessary for activity although the 4-deoxy derivatives were less potent than the 4-hydroxy diterpenes. A primary hydroxy group at C-20 was essential for biological activity because the methyl and aldehyde derivatives of this position were inactive. The C-20 acetates were also inactive on platelets, but they did produce erythema, possibly because of the removal of the ester due to lipase activity in the skin. 5-hydroxy-analogues which undergo intramolecular hydrogen bonding had greatly reduced activities in both systems. Membrane stabilisers, phospholipase A2 and calmodulin inhibitors were antagonists for phorbol esters in platelet aggregation tests, whilst cyclo-oxygenase inhibitors and free radical scavengers had no inhibitory effects. Consequently, one electron withdrawal and free radical formation plays no part in the biological activity of these compounds.
Studies on the mechanism of action of 12-deoxyphorbolphenylacetate, a potent platelet aggregating tigliane ester.
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Vascular changes in rabbit skin induced by proinflammatory phorbol and 12-deoxyphorbol esters.
The effects of proinflammatory phorbol and 12-deoxyphorbol esters were determined on blood flow changes and plasma exudation in rabbit skin. Blood flow changes were measured by means of 133Xe washout over that in control-treated sites, while plasma exudation was measured by 131I-labeled human serum albumin leakage from skin blood vessels. 12-Deoxyphorbol-13-phenylacetate, 12-deoxyphorbol-13-angelate, and their C-20 acetates induced vasoconstriction in rabbit skin in doses of 100 ng/site. Tetradecanoyl phorbol acetate indiced vasoconstriction to a far lower degree, while the parent alcohol phorbol and 9,13,14-orthophenylacetyl-resiniferonol had no significant effects on rabbit microvasculature. The ability of tigliane esters to contract rabbit blood vessels was confirmed in vitro in that each of these esters induced a prolonged contraction of superfused rabbit aorta in doses of 1-5 microgram. Plasma exudation in rabbit skin was not significantly increased by the phorbol and 12-deoxyphorbol esters, but in a second determination using 100 ng of PGE1 together with 100 ng of ester, plasma exudations of up to 40 microliter per site were recorded.
Inhibition of erythema induced by pro-inflammatory esters of 12-deoxyphorbol.
The pro-inflammatory tigliane esters 12-deoxyphorbolphenylacetate (12-DOPPA) and 12-deoxyphorbolphenylacetate-20-acetate (12-DOPPAA) at a dose of 0.1 microgram induced erythema in the mouse ear. Observations of ear redness were made both two and four hours after application. Indomethacin was only partly successful as an antagonist since 10% inhibition of 12-DOPPA and no inhibition of 12-DOPPAA induced erythema was produced four hours after application. The free radical scavengers, phenol, thioanisole and sodium benzoate all produced less than 30% inhibition of 12-DOPPA induced erythema and less than 15% inhibition of 12-DOPPAA, whereas aminopyrine produced 70% and 25% inhibition of 12-DOPPA and 12-DOPPAA respectively. The fact that free radical scavengers (with the exception of aminopyrine) and indomethacin, failed to markedly change the mouse ear reaction to 12-deoxyphorbol esters, indicated that this erythema is not entirely mediated via cyclooxygenase products. Mepyramine and cyproheptadine also failed to inhibit the erythema, whereas hydrocortisone produced a 55% inhibition of the 12-DOPPA and a 20% inhibition of the 12-DOPPAA reaction. The membrane stabilising agents trifluoperazine, promethazine, imipramine and desmethylimipramine were the most successful compounds used in inhibiting both 12-DOPPA and 12-DOPPAA induced erythema. In addition propranolol, which inhibits stimulus activation of phospholipase A2, produced 70% and 55% inhibition of the reaction of mice ears to 12-DOPPA and 12-DOPPAA.
Inhibition of histamine-induced acid secretion in rat isolated gastric mucosa by esters of phorbol and 12-deoxyphorbol.
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Constituents of Egyptian Euphorbiaceae. IX. Irritant and cytotoxic ingenane esters from Euphorbia paralias L.
The irritant and cytotoxic constituents of the latex of Euphorbia paralias L. were separated from the hydrocarbon fraction by means of solvent partition. 3 new ingenane esters were identified from the toxic ether fraction. The major compound was 3-angelyl-20-deoxyingenol and the 2 minor compounds were 3-hexanoyl-20-deoxyingenol and 3-angelyl-ingenol. These compounds were of a similar potency to podophyllin in the inhibition of 3H-thymidine uptake by TLX/5 mouse lymphoma cells. In addition the compounds produced a persistent erythema of the mouse ear in sub-microgram doses.
The effect of daphnane esters on platelet aggregation and erythema of the mouse ear.
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Pericentric inversion (13) with two different recombinants in the same family.
A family is described in which a pericentric inversion (13) was discovered in the father after the birth of an abnormal baby. In a further pregnancy amniocentesis was carried out. The fetal karyotype showed a rec(13)dup p,inv(13)(p11q22). The fetus's abnormalities were similar to those observed in the first child. Family studies showed that a first cousin, mentally retarded, had a rec(13)dup q,inv(13)(p11q22) karyotype. In this family, the risk of occurrence of a recombinant in offspring of an inversion carrier could be as high as 40%.