Search

Whereas low doses of aspirin relieve most minor aches and pains, high doses are used to treat chronic inflammatory diseases such as rheumatoid arthritis. Is there any physiological basis for the different effects at high doses? According to a new study there is. High doses of aspirin inhibit IKB kinase-b(IKK-b), and these results may help us to separate the therapeutic benefits of high-dose aspirin from its toxic side effects.

MCGEER and McGeer1 recently reported that an intrastriatal injection of glutamate results in biochemical changes in brain similar to those associated with Huntington's chorea. They postulated that glutamate, a putative excitatory transmitter and an ‘excitotoxin’ abundantly present in brain may have a role in the pathophysiology of Huntington's chorea. Their evidence for this postulate must be considered very preliminary, however, as the biochemical changes induced by a 50 nmol dose of glutamate were not striking and it was not determined whether these changes were accompanied by neuronal degeneration1. We have, injected various doses of glutamate directly into the rat striatum and examined the striatum for histopathological changes 21 d later. Here we report that doses of glutamate much higher than 50 nmol definitely cause striatal neurones to degenerate, whereas no neurotoxic reaction results from injecting equally high doses of control compounds such as NaCl or γ-aminobutyric acid (GABA).

THE potential of α-chlorohydrin (3-chloro-1,2-propanediol; Fig. 1a) as an orally active reversible male antifertility agent has been demonstrated in the rat1,2, ram3 and boar4. Adverse side-effects, however, particularly in the monkey5, have precluded human trials and for this reason, elucidation of the mechanism of action6,7 of α-chlorohydrin is clearly important in order to develop less toxic yet more active antifertility analogues. Although high doses obstruct the lumen of the caput epididymis of the rat2, the initial and primary contraceptive effect seems to be directly on spermatozoa within the cauda epididymis8–11.

IN mice injected with mouse-passaged scrapie, the earliest rise in titre of agent is found in organs of the lymphoreticular system—irrespective of whether the injection is intracerebral or by a peripheral route1–4. The titre of agent in the spleen, for example, can rise fairly quickly to a moderate plateau level and subsequently starts to increase progressively in the brain, where it reaches, during the clinical phase, a greater concentration than elsewhere. These generalisations are based on work in various laboratories with agent strain–mouse strain combinations having relatively short incubation periods in the range 150–300 d after injection of high doses of agent. Evidence of replication in the spleen is therefore an indication that the animal will eventually develop scrapie if it lives long enough.

A MONTHLY application of contraception has the advantage that it involves application of medication only in the event of suspected pregnancy such as delayed menses1, thereby reducing the unnecessary exposure of healthy persons to drugs. An intravaginal application of prostaglandins (PGs) has been successfully used for this purpose in 11 women1. Naturally occurring PGs need to be administered in high doses to obtain termination of pregnancy by the oral route, however, and the effective doses have side effects such as vomiting, nausea and diarrhoea1. It would be desirable to develop an analogue of natural PG active orally in doses which have no undesirable side effects, and with this rationale in mind we developed a C-22 derivative (Fig. 1) of PGF2α—ICI 74,205 which appears to be some 20 times more potent orally than the parent PG in terminating early pregnancy in hamsters.

ADENOSINE triphosphate (ATP) and related adenosine phosphates cause bronchoconstriction in guinea-pig isolated lungs, and, in relatively high doses, increase air overflow volume in the Konzett-Rossler preparation of guinea-pig lungs in vivo1. ATP elicits pain in man when applied to an exposed blister base2, as do several other endogenous substances that induce bronchoconstriction in the guinea-pig. We have confirmed that ATP increases air overflow volume in the Konzett-Rossler preparation of the guinea-pig and we have found that, in keeping with its algogenic action in man, ATP induced a nociceptive response in mice. Both the bronchoconstrictor and the nociceptive responses were antagonized by salts of aspirin and of three aryl anthranilic acids (flufenamic3, mefenamic4 and meclofenamic5), which we shall collectively call ‘fenamates’.

CATECHOLAMINES, especially noradrenaline, are regarded as central neuro-humoral agents of ergotropic character1–3. Notwithstanding, parenterally injected adrenalin has a depressive effect in intact animals, at least in relatively high doses, causing, in certain conditions, even sopor or general analgesia. Similar effects have been observed also after injections of catecholamines into the sub-arachnoideal space, the ventricles or the cerebral tissue2.

THE incidence of schizophrenia in most communities is of the order of 1 per cent. Yet the fertility of schizophrenic males is low, as noted by Huxley et al.1; and it has since been established that the fertility of schizophrenic females is low, too2. The second observation serves to strengthen the suggestion of Huxley et al. that the fertility of schizophrenics seems too low for the disorder to be maintained at its present rate by mutation alone. In explanation they noted the resistance of schizophrenics to surgical and wound shock, to visceral perforation, to high doses of histamine, insulin and thyroxine, and to pain. They noted also the possibility that schizophrenics may be resistant to diseases such as smallpox and bubonic plague which have occurred in widespread epidemics.

YOHIMBINE in fairly high doses (2–7 mgm./kgm.) exerts adrenolytic effects and is sympatholytic for salivary reactions in animals1–5. Higher doses (28 mgm./kgm.) produce sympatholysis of nictitating membrane retraction, while even more is required for sympatholysis of mydriatic action2,3.

IT was not until recently that a method for the quantitative estimation of erythropoiesis became available1. The method introduced requires the application of high doses of radioactive iron, a very stable and sensitive measuring equipment and protracted measurements. The authors showed that the usual calculation of erythrocyte formation from plasma iron-turnover (PIT) values is frustrated by a substantial return of radioiron from the bone marrow into the plasma, starting at about 8 h after injection of radioiron. This finding and the results of Lamerton et al.2 induced me to block the re-utilization of radioiron by injecting inactive iron. Under such conditions PIT would correctly measure iron uptake by the organs of the body, and the radioiron incorporation into erythrocytes would be a correct indicator of the amount of iron built in into erythrocytes. The quotient between the amount of iron contained in the total circulating haemoglobin and the amount built in into erythrocytes would then be a measure of the effective life-time of the erythrocytes.

VERY little information is available on the effects of neutrons on mutagenesis in female germ cells. In mice, published work with fast neutrons at high and low intensities has been confined to the irradiation of spermatozoa for the induction of dominant lethals1, and to spermatogonia for specific locus mutations2,3. In insects, however, relative biological effectiveness (RBE) of 2–4 has been demonstrated in Mormoniella adult females for recessive eye colour mutants following high doses of fission neutrons4, and higher values for low doses. Similarly, acute doses of 14 MeV neutrons have an RBE of 1.2 for recessive visible mutations in silkworm oogonia5, while fission neutrons have RBEs of 2.5–3 (ref. 6). This communication presents data on the mutagenic effects of 14 MeV neutrons as compared to cobalt-60 gamma rays in adult females of Dahlbominus fuscipennis.

Frogs and toads treated with high doses of anthracene-9-carboxylic acid (A-9-C) develop prolonged muscular contrac-tions and ‘divebomber’ electromyograms characteristic of myotonia. Hitherto, myotonia has been considered peculiar to homeotherms where it is associated with several hereditable diseases and can be induced by specific treatments, most of which seem to act by decreasing membrane chloride conductance1. Our work indicates that myotonia can be induced in amphibia by similar means. We offer possible reasons why others have missed seeing myotonia in amphibia.

THE spatial pattern of cellular differentiation in the chick limb can be viewed in terms of positional information. For the antero–posterior axis of the wing, positional information seems to be specified by reference to a group of cells at the posterior margin of the limb bud—the zone of polarising activity (ZPA)1–3. By grafting an additional ZPA to different positions along the antero–posterior axis, we found that structures form according to their distance from the nearest ZPA. For instance, digit 4 forms nearest to the ZPA, then digit 3, then digit 2. We suggested that cells might measure distance by means of a diffusible morphogen produced by the ZPA, the concentration of which falls as distance from the ZPA increases. The responding cells are able to interpret the concentration of the morphogen, and so behave according to their position. If it is the concentration of morphogen that specifies which digit shall form, then lowering the concentration of morphogen adjacent to the ZPA should result in digit 3 being formed next to the ZPA instead of digit 4. If the concentration is lowered still further, digit 2, and finally no additional digit should form next to the ZPA. We have obtained such an attenuation of positional signalling by treating the ZPA with increasing doses of γ radiation.

THE synthetic analogue of methionine enkephalin, FK 33-824, exerts a long-lasting and potent analgesic effect in animals after systemic and enteral administration1. In high doses it produces tolerance, cross-tolerance with morphine, and dependence in monkeys. Like β-endorphin, FK 33-824 produces akinaesia in rats and rabbits. All effects seen in animals can be abolished by naloxone. We report here on the results of the first studies performed with FK 33-824 in man (tolerance, electroencephalogram (EEG), endocrine profile and plasma levels), as a basis for future therapeutic studies.

IT has been shown in this laboratory that under some experimental conditions the homologous bone marrow treatment may be successful in preventing fatal bone marrow aplasia induced by high doses of ‘Myleran’1,2. On the other hand, it is well known that a number of lethally whole-body irradiated mammals, which survive the first 30 days after exposure, thanks to homologous or heterologous bone marrow transfusions, may succumb during the second and third month3,4. This delayed mortality known as secondary disease is attributed by several investigators to an immunological reaction of the graft versus the host. Some success has been reported in preventing or treating the secondary disease in irradiated animals by various means5–10. In this communication the preliminary results concerning absence of secondary disease in rats treated with homologous bone marrow transfusions after administration of ‘Myleran’ are given.

IT seems to be well established that even at high doses X-rays induce practically no translocations in oocytes of Drosophila melanogaster, although they do produce detachments of the attached X-chromosome. Glass1 and Thomas and Roberts2 discuss possible reasons for this peculiar phenomenon. So far only relatively high doses (for example, 4,500 r. in the work of Kanellis and Radu3) have been used, a procedure which appears to be most promising at first sight because translocations are ordinarily produced by two hits.

Ephestia kuhniella Z., the meal moth, proved to be a good object for investigation of quantitative relations between somatic mutations and ionizing radiations1,2. These former investigations were concerned with relative high doses (100–1,000 r.). It seemed interesting to extend the experiments to the lower dose-range, since there is a complete lack of knowledge of this part of the dose effect curves of somatic mutations in animals.

THE effects of ovarian hormones on the cell cycle of target tissues have been extensively studied. It has been shown that high doses of oestrogens of exogenous origin can alter the duration of DNA synthesis (S phase) in target tissues when administered alone1,2 or in association with progesterone3.

IT is known that rats fed on a diet containing 50 per cent sweet-pea (Lathyrus odoratus) seed develop severe bony deformities, and that if young animals are used a proportion die of rupture of the aorta1,2; β-amino-propionitrile has a similar effect3. Few workers had previously attempted to produce lathyrism in mice, and their reports suggested that mice were refractory. Preliminary experiments, however, showed that aortic lesions in mice could be obtained, and while this work was in progress Dasler and Milliser4 reported the production of aortic lesions in male weanling mice by feeding them on L. odoratus seeds ; injection of high doses of β-amino-propio-nitrile gave, in addition, bony lesions. Experiments were continued with the aim either of confirming Dasler and Milliser's work and producing lathyrism in a cheap and easily handled animal or, if the mouse were resistant, of using this difference in response between two such closely related species as the rat and the mouse for investigation of the pathogenesis of lathyrism.

ACTINOMYCIN D (AMD) has been shown to inhibit the ribonucleic acid (RNA)-polymerase activity of bacterial cells. This inhibition is considered, at present, to represent the sole mechanism by which this agent inhibits cell division1. It appears to result from the formation of complexes between the antibiotic and deoxyribonucleic acid (DNA)2. Following parenteral administration to animals the antibiotic appears to possess similar activity, but differs in that high doses are required and the effects are reversible3. When administered to rats which have undergone partial hepatectomy, the expected subsequent mitotic activity can be eliminated4.

RECENT experimental evidence has demonstrated that high doses of synthetic sweeteners cause bladder cancer in rodents. In rats, the oral administration of a cyclamate–saccharine mixture alone or combined with cyclohexylamine, a metabolite of cyclamate, induced a high frequency of bladder carcinoma1. These tumours also developed in mice after bladder implantation of cholesterol–cyclamate or cholesterol–saccharine pellets1,2. These studies prompted the Department of Health, Education and Welfare to restrict the general use of cyclamates and to undertake further laboratory studies on the toxicity of synthetic sweeteners. As a first step in evaluating whether synthetic sweeteners are carcinogenic in man, we have examined the consumption patterns of these agents and the trends for bladder cancer in the United States.

There are two types of high background areas in Brazil where the thorium content of the soil is high. These are regions of monozite sands in the states of Rio de Janeiro and Espirito Santo and regions of volcanic intrusives in the state of Minas Gerais. These areas of high background radiation afford great possibilities for investigations of long-term consequences to biological systems of continuous exposure to relatively high doses of radiation. (C.E.S.)

THE anaphylactoid reaction caused by dextran in rats has recently been studied by several investigators1–3. We have found that after intradermal injections of dextran dissolved in physiological saline (in rats), Menkin's intravenous dye test4 shows a seepage of dye into the wheals when the concentration of commercial dextran (Macrodex, Pharmacia Inc.) is at least 10 µgm/ml. Moreover, it has been found that dextran preparations with highly branched molecular chains are more toxic than those with relatively unbranched chains. Dextran fractions of an average molecular weight of 10,000 cause a positive dye test only in concentrations of about 10 mgm./ml. Sulphuric acid esters of dextran5 do not cause increased capillary permeability. We have confirmed the previously reported increase in haematocrit values after intravenous injection of dextran3, and found that it is more or less completely prevented by antihistaminics, local anaesthetics and pretreatment with cortisone in high doses. The most potent inhibitor, however, is alloxan intravenously in a subdiabetogenic dose. 2,3-Dimercaptopropanol injected 30 min. before dextran has an inhibitory effect only in some experimental series. The factors causing these variations in the ‘antiphlogistic’ effect of BAL are under study.

DRUMMOND-ROBINSON and Asdell1 showed that ablation of the corpora lutea in the pregnant goat caused milk secretion provided the operation was done after the development of the mammary lobule-alveolar system. This suggests that the corpus luteum inhibits lactation prior to parturition, though the work of Anselmino et al.2,3 indicates that the inhibitor is different from the hormone which causes proliferation of the uterine endometrium. On the other hand, Frei and Gruter4 reported that injections of suspensions of corpus luteum tissue exerted a favourable effect on lactation in the cow. The experiments reported briefly below confirm the contention of Anselmino et al., since we have found that administration of relatively high doses of pure progesterone to the lactating rat does not inhibit lactation as judged by the rate of growth of sucklings.

IT has been reported1 that paramagnetic centres are produced in glycine by equal doses of γ-rays, fast neutrons and α-particles in the proportions 1 : 0.7 : 0.1. As the lower efficiency of the α-particles might well be due to the high linear energy transfer along their tracks, an investigation of the effects of very high doses of electrons on the electron spin resonance spectrum of glycine and related substances seemed worth while.