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Biomedical subjects

D F Horrobin

Publications and source records attributed to D F Horrobin.

At least 253 records · Page 14Linked to original sources
PubMed1981

The possible effect of diazepam on cancer development and growth.

Diazepam has the characteristics of a tumour promoter in a number of in vitro systems. The effect is apparent at concentrations of diazepam which are clinically relevant. Diazepam also accelerated tumour growth in two different experimental animal cancers. Tranquillizer use was found to be greater in women with metastatic breast cancer at the time of diagnosis than in those without metastases. Further evaluation of the possible effects of diazepam and related drugs on human and animal cancers is urgently required.

Animals↗
PubMed1981

Loss of delta-6-desaturase activity as a key factor in aging.

Aging is characterized by a wide variety of defects, particularly in the cardiovascular and immune systems. Cyclic AMP levels fall, especially in lymphocytes. Delta-6-desaturase (D6D) levels have been found to fall rapidly in the testes and more slowly in the liver in aging rats. D6D is an enzyme which converts cis-linoleic acid to gamma-linolenic acid (GLA). Other factors which inhibit D6D activity are diabetes, alcohol and radiation, all of which may be associated with accelerated aging. In meat eaters or omnivores which can acquire arachidonic acid from food, the main consequences of D6D loss will be deficiencies of GLA, dihomogamma-linolenic acid (DGLA) and prostaglandin (PG) E1. PGE1 activates T lymphocytes, inhibits smooth muscle proliferation and thrombosis, is important in gonadal function and raises cyclic AMP levels in many tissues. It is a good candidate for a key factor lost in aging. Moderate food restriction, the only manoeuvre which consistently slows aging in homoiotherms, raises D6D activity by 300%. Other factors important in regulating D6D and the conversion of GLA to PGE1 are zinc, pyridoxine, ascorbic acid, the pineal hormone, melatonin, and possibly vitamin B3. GLA administration to humans has been found to lower blood pressure and cholesterol, and to cause clinical improvement in patients with Sjogren's syndrome, scleroderma and alcoholism. These diseases are associated with some features of accelerated aging. The proposition that D6D loss is not only a marker of aging but a cause of some of its major manifestations is amenable to experimental test even in humans. The blocked enzyme can be by-passed by giving GLA directly.

15-Oxoprostaglandin 13-Reductase↗
PubMed1980

Possible role of prostaglandin E1 in the affective disorders and in alcoholism.

Prostaglandin (PG)E1 may play an important part in the affective disorders, with an excess being present in mania and a deficiency in depression. Platelets from manic patients produce more PGE1 than normal while those from depressive patients produce less. Ethyl alcohol stimulates PGE1 production whereas lithium inhibits it. Alcoholics will tend to have raised PGE1 concentrations while drinking, but, because precursor supplies are limited, when alcohol concentrations fall PGE1 concentrations may fall sharply leading to depression. PGE1 biosynthesis may be affected by nutritional factors including essential fatty acids, pyridoxine, vitamin C, and zinc. Nutritional approaches may be of value in both depression and alcoholism.

Affective Symptoms↗
PubMed1980

Thromboxane A2 in blood vessel walls and its physiological significance: relevance to thrombosis and hypertension.

It has been thought that blood vessels apart from the umbilical artery produce little or no thromboxane (TX) A2. However selective inhibitors of TXA2 biosynthesis have substantial effects on vessel physiology, suggesting that small amounts of TXA2 may be important in regulating function. This indirect evidence is now supported by direct measurements of TXB2 (the produce of TXA2 conversion) using both gas chromatography-mass spectrometry (GCMS) and radioimmunoassays. At least four independent laboratories have now demonstrated TXB2 production by various blood vessels. These studies suggest that vessel wall TXA2 is present in amounts more than adequate to exert biological actions on both vascular reactivity and on platelets. This may require re-evaluation and revision of present concepts of hypertension and thrombosis.

Animals↗
PubMed1980

16, 16 dimethyl PGE2: evidence that it has properties different from the parent compound in vascular smooth muscle.

16, 16 dimethyl PGE2 (dmPGE2) differs from its parent compound, PGE2, in the way in which it affects vascular reactivity in the isolated perfused mesenteric vascular bed of the rat. Increasing concentrations of PGE2 progressively increase response amplitudes to both noradrenaline and potassium but have no effect on baseline pressure. PGE1 does not change potassium responses but has a biphasic effect on noradrenaline responses, increasing them at low concentrations and inhibiting them at high ones: it has no effect on baseline pressure. PG12 progressively inhibits noradrenaline responses but has no effect on potassium responses: it does not influence baseline pressure in this preparation. PGF2 alpha, like PGE2, enhances responses to both noradrenaline and potassium but, unlike PGE2, strongly elevates baseline pressure. dmPGE2 progressively enhanced responses to potassium, had a biphasic effect on responses to noradrenaline, and strongly raised baseline pressure. Its effects were therefore different from PGE2 and shared properties of the other PGs. This analogue must be used with caution as a guide to the physiological effects of PGE2 itself. The superior mesenteric preparation, which responds very differently to different PGs may be a valuable tool for determining the changes in properties brought about by manipulation of the parent PG molecules.

16,16-Dimethylprostaglandin E2↗
PubMed1980

A new concept of lifestyle-related cardiovascular disease: the importance of interactions between cholesterol, essential fatty acids, prostaglandin E1 and thromboxane A2.

A proposal to account for the inter-relationships between established risk factors and cardiovascular disease is presented. In this concept, the critical substance is prostaglandin (PG) E1 which is a vasodilator, an inhibitor of platelet aggregation, an inhibitor of cholesterol and collagen biosynthesis and an inhibitor of smooth muscle proliferation. PGE1 biosynthesis is enhanced by the essential fatty acid, linoleic acid, by the platelet aggregating agent thromboxane (TX) A2, by cholesterol and by melatonin. These factors may participate in a negative feedback control loop. As a result of the operation of this loop, any tendency for PGE1 levels to fall is followed by increased cholesterol and TXA2 biosynthesis, and enhanced platelet aggregation, vasoconstriction, smooth muscle proliferation and collagen biosynthesis. Enhancement of PGE1 biosynthesis will have the opposite effects. Factors known to increase PGE1 biosynthesis include essential fatty acids, vitamin C, ethanol, pyridoxine, zinc and probably niacin, all of which are known to have some protective effects against cardiovascular disease. The hypothesis predicts that lowering of cholesterol biosynthesis by any method other than enhanced PGE1 formation, while reducing the risk of cardiovascular disease, will increase the risk of other disorders. The hypothesis suggest new approaches to treatment and new ways of combining existing treatments. Colchicine, which at low concentrations may imitate and action of melatonin, has particularly interesting possibilities. Colchicine and related compounds have already been shown to have potent cholesterol-lowering and anti-atherogenic actions in both humans and animals.

Cardiovascular Diseases↗
PubMed1980

A biochemical basis for alcoholism and alcohol-induced damage including the fetal alcohol syndrome and cirrhosis: interference with essential fatty acid and prostaglandin metabolism.

Alcohol has at least two actions on essential fatty acid (EFA) and Prostaglandin (PG) metabolism. It enhances the conversion of dihomogammalinolenic acid (DGLA) to PGE1 but it blocks the activity of the delta-6-desaturase, an enzyme necessary for replenishment of DGLA stores from dietary precursors. The acute effect of ethanol is therefore an increased production of PGE1 but chronic consumption will lead to depletion of DGLA and PGE1. Withdrawal from alcohol will lead to a precipitous fall in PGE1. PGE1 is known to have profound effects on the nervous system and behaviour. Patients with mania produce more PGE1 than normal while those with depression make less. Alcoholics may drink to maintain a normal PGE1 level, something which will require more and more ethanol as DGLA is depleted. In both animals and humans PGE1 or its precursor, gamma-linolenic acid (GLA) have been shown to attenuate the acute withdrawal syndrome. PGE1 injections prevent the development of fatty liver in alcohol-treated animals. Defective EFA and PGE1 metabolism are known to lead to increased fibrosis, reproductive failure, cardiomyopathy, cardiovascular disorders, gastritis and pancreatitis and could therefore be the basis for these disorders in alcoholics. A PGE1 deficiency could also be responsible for the fetal alcohol syndrome. Three other agents are known to produce constellations of fetal defects very similar to those found in the alcohol syndrome. These other factors are dihphenylhydantoin, lithium, and a deficiency of zinc. These three factors and excessive alcohol consumption all lead to PGE1 deficiency by different routes. If this concept is correct, the key to the management of alcoholism and its medical complications lies in the provision of GLA or DGLA, fatty acids which by-pass the alcohol blocked step and which are unfortunately unlikely to be present in any normal diet. Unlike many concepts of alcoholism and alcohol damage, the EFA/PGE1 idea is very readily testable and already has considerable experimental support.

8,11,14-Eicosatrienoic Acid↗
PubMed1980

Myotonic dystrophy: a disease caused by functional zinc deficiency due to an abnormal zinc-binding ligand?

There are large amounts of zinc in muscle and zinc ions can enhance the degree of muscle contraction in response to direct stimulation while at the same time inhibiting neuromuscular transmission. The opposites of these effects would lead to myotonia and muscle weakness. There are many parallels between the non-muscular features of myotonic dystrophy and those of zinc deficiency. The particular patterns of reproductive disturbance in both males and females, the abnormalities of metabolism, the defects in gut funcion, the defects in bone and the congenital abnormalities are very similar in the two conditions. However there are important differences between simply zinc deficiency states and myotonic dystrophy which mean that the latter is unlikely to be due to the former. Instead it is proposed that the fundamental defect in myotonic dystrophy is the presence of an abnormal zinc binding ligand which fails to deliver appropriate amounts of zinc ions to the tissues. The functioning of this ligand may, however, be affected by dietary zinc, perhaps accounting for the apparent variation in the expression of the dominant myotonic dystrophy gene due to some unknown environmental factor. Some of the effects of zinc may be due to lack of the zinc ion directly, while others are probably related to defects in essential fatty acid and prostaglandin metabolism. The hypothesis can be readily tested by the employment of nutritional measures designed to counteract the defects in zinc and essential fatty acid metabolism.

Bone Diseases↗
PubMed1980

The reversibility of cancer: the relevance of cyclic AMP, calcium, essential fatty acids and prostaglandin E1.

Transformed cells in culture can be normalised (made to undergo reverse transformation) by exposure to cyclic AMP, prostaglandin (PG) E1 and certain drugs. One of these drugs, thioproline, has been successfully used in treating human cancer. All cancer cells have a number of common characteristics: they exhibit aerobic glycolysis, they fail to show feedback regulation of cholesterol biosynthesis, they do not regulate cytoplasmic calcium levels normally and they produce excessive amounts of 2 series PGs. It has been known since 1975 that transformed cells cannot make PGE1 because of loss of the delta-6-desaturase enzyme which converts linoleic acid to gamma-linolenic acid. There is evidence that PGE1 acting in concert with thromboxane A2 has effects which make it able to reverse all the metabolic abnormalities common to all cancer cells. It is therefore argued that loss of the ability to make PGE1 and/or thromboxane A2 may be the critical step in malignant change in many forms of cancer. Restoration of normal PGE1 synthesis by providing gamma-linolenic or dihomogammal inolenic acids which will by-pass the blocked desaturase, whould be of value in normalising malignant cells and reversing cancer growth. Since this approach is completely non-toxic it is here seriously suggested that it might be used as a first step in treatment of those cancers where current evidence suggests that delay in the administration of orthodox treatment is unlikely to affect prognosis.

Animals↗
PubMed1980

Sjogren's syndrome and the sicca syndrome: the role of prostaglandin E1 deficiency. Treatment with essential fatty acids and vitamin C.

Lack of adequate synthesis of prostaglandin (PG) E1 may be the key factor in Sjogren's syndrome. PGE1 is important for lacrimal and salivary gland secretion and for T lymphocyte function: a deficiency could therefore account for the main features of Sjogren's syndrome and the sicca syndrome. PGE1 could also account for many of the other features often associated with these syndromes. These include the Raynaud's phenomenon, the abnormalities of renal function and the precipitation of the syndrome by vitamin C deficiency. Vitamin C is important in PGE1 biosynthesis. PGE1 treatment has been shown to correct the immunological abnormalities in the NZB/W mouse, the animal model of Sjogren's syndrome. An attempt to treat humans with Sjogren's syndrome by raising endogenous PGE1 production by administration of essential fatty acid PGE1 precursors, of pyridoxine and of vitamin C was successful in raising the rates of tear and saliva production.

Arthritis, Rheumatoid↗
PubMed1980

Interactions between zinc, essential fatty acids and prostaglandins: relevance to acrodermatitis enteropathica, total parenteral nutrition, the glucagonoma syndrome, diabetes, anorexia nervosa and sickle cell anaemia.

Many of the features of zinc deficiency and of essential fatty acid (EFA) deficiency are similar in both animals and humans. The two agents interact in various ways. EFAs are important in zinc absorption, probably after conversion to prostaglandins (PGs). Zinc seems necessary for at least two stages in EFA metabolism, the conversion of linoleic acid to gamma-linolenic acid, and the mobilisation of dihomogammalinolenic acid (DGLA) for the synthesis of 1 series PGs. Zinc may also be important in the conversion of DGLA to arachidonic acid and in arachidonic acid mobilisation for 2 series PG formation. These interactions shed considerable light on a number of clinical syndromes, including acrodermatitis enteropathica, total parenteral nutrition, diabetes mellitus, the glucagonoma syndrome and sickle cell anaemia. There is substantial evidence to suggest that anorexia nervosa is due to a combined deficiency of zinc and EFAs. Understanding of the roles of zinc and EFAs in these various clinical situations is likely to lead to improved therapy.

Acrodermatitis↗
PubMed1980

Enhanced vascular reactivity to various vasoconstrictor agents following pinealectomy in the rat: role of melatonin.

The mesenteric vascular bed preparation of control and pinealectomized (PX) male Wistar rats was used to examine vascular reactivity to two concentrations each of norepinephrine, serotonin, angiotensin, and potassium. Vasoconstrictor responses to 50- and 100-ng injections of norepinephrine and 0.5- and 1.0-microgram injections of serotonin were 30-40% higher in preparations from PX rats. Reponses to 100 ng but not to 50 ng of angiotensin were also significantly higher in preparations from PX rats. Responses to 1.5- and to 3.0-mg injections of potassium did not differ significantly in either case. In vivo injection of 20 microgram of melatonin 3 h prior to dissection of the preparation, or in vivo perfusion of 20 ng melatonin per millilitre of buffer completely reversed the increased vascular response to all vasoconstrictor agents tested in the PX preparations, but had little effect in control preparations. Also observed in PX rats was a significant increase in blood pressure, serum sodium, and increased body and heart weight. Arterial wall sodium was also elevated in PX rats. These changes may be relevant to the increased vascular reactivity of PX rats. The increased vascular responsiveness of PX rats may be specific for agents that stimulate calcium release from intracellular stores (norepinephrine, angiotensin) rather than those that stimulate calcium influx from extracellular fluid (potassium). Melatonin lack may be the cause of the vascular changes in the PX rats as both in vivo and in vitro it lowered the vasoconstrictor effects of the agents tested, but only in PX rats; it had no significant effect in the control rats.

Angiotensin II↗