Biomedical subjects
Publications and source records attributed to M Williams.
Increasing numbers of women are embarking on more strenuous and constant exercise; their menstrual patterns are changing as a result. This review of the literature indicates that oligomenorrhoea and amenorrhoea in the physically active (particularly distance runners, gymnasts, ballet dancers and swimmers) are related to each woman's physiological and psychological makeup.
The (+)-enantiomer of 1,2,3,4a,5,6-hexahydro-9-hydroxy-4-n-propyl-4H-naphth[1,2-b][ 1,4]-oxazine [(+)-PHNO] is demonstrated to be a potent and direct dopamine (DA) agonist in several in vivo and in vitro test procedures. In vitro (+)-PHNO inhibited binding of [3H]apomorphine (IC50 = 23 nM) or [3H]spiperone (IC50 = 55 nM) to rat striatal membranes. Because (+)-PHNO failed to stimulate adenylate cyclase in carp retina, it was classified as a D-2 agonist. ED50 values (shown in parentheses) derived in DA receptor-related in vivo tests were as follows: in mice, (+)-PHNO produced hypothermia (13 micrograms/kg i.p.) and postural asymmetry in the unilaterally caudectomized animal (4 micrograms/kg i.p.). In the rat, (+)-PHNO produced stereotypy (10 micrograms/kg i.p.) and contralateral turning in 6-hydroxydopamine-lesioned animals (5 micrograms/kg i.p.) that lasted 1 to 3 hr. Whereas both of the latter effects were blocked by haloperidol, prior treatment with depletors of endogenous catecholamines, reserpine or alpha-methylparatyrosine failed to reduce (+)-PHNO-induced stereotypy. The naphthoxazine also produced emesis in beagles (0.05 micrograms/kg i.v.) that was blocked by L-646,462, a peripherally selective DA receptor antagonist. (+)-PHNO was well absorbed when given p.o., producing contralateral turning (10 micrograms/kg) with a ratio of p.o. to i.p. ED50 values of 2. This ratio was much lower than those derived for n-propylnorapomorphine (60) and apomorphine (54). At the DA autoreceptor, (+)-PHNO inhibited the accumulation of dOPA in the gamma-butyrolactone-treated rat (11 micrograms/kg i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)
The nicotinic cholinergic antagonist, dihydro-beta-erythroidine, binds to two sites in rat cortical membranes with dissociation constants of 4 and 22 nM and respective apparent Bmax values of 52 and 164 fmol/mg of protein. Binding to the higher affinity site, defined by the use of 2 nM [3H]dihydro-beta-erythroidine, was saturable, reversible, and susceptible to protein denaturation. Binding was highest in the thalamus and lowest in the spinal cord and showed preferential enrichment in a synaptosomal subfraction of rat brain. Nicotine displaced [3H]dihydro-beta-erythroidine in a stereospecific manner, the (-)-isomer being approximately 6 times more potent than the (+)-isomer. The alkaloid nicotinic agonists, cytisine and lobeline, were potent inhibitors of binding, while acetylcholine in the presence of the cholinesterase inhibitor di-isopropylfluorophosphate was equipotent with (+)-nicotine. Binding was also inhibited by the muscarinic ligands, arecoline, atropine, and oxotremorine. The nicotinic antagonists mecamylamine, hexamethonium, and pempidine were essentially inactive in displacing [3H]dihydro-beta-erythroidine. These findings indicate that dihydro-beta-erythroidine binds to a nicotinic recognition site in rat brain which is neuromuscular, rather than ganglionic, in nature and that such binding is similar in several respects to that seen with nicotinic agonists. Whether such binding is to a nicotinic, as opposed to nicotinic cholinergic, recognition site or to a "common" nicotinic/muscarinic site is an issue that requires further study.
The selectivity, peripheral vs. central actions, of the antidopaminergic agent L-646,462 was assessed in two ways. First, elevation of prolactin in serum (peripheral) and homovanillic acid in the striatum were measured in rats. L-646,462 was found to have a central/peripheral activity ratio of 143, whereas comparable values derived for haloperidol, metoclopramide and domperidone were 1.4, 9.4 and 1305, respectively. Second, the ID50 values required to block apomorphine-induced emesis in beagles (peripheral receptor-mediated response) were compared with those required to block apomorphine-induced stereotypy (central receptor-mediated response) in rats. Central/peripheral ID50 ratios of 234, 9.2, 129 and 7040 were obtained, respectively, for L-646,462, haloperidol, metoclopramide and domperidone. The selectivity of L-646,462 for peripheral serotonin (5-HT) receptors in rats was determined by measuring its effectiveness in blocking 5-HT-induced paw edema (peripheral response) and 5-hydroxytryptophan-induced head twitch (central response); a ratio of 114 was obtained. This value agrees nicely with the ratio of 143 derived in the rat ( vide supra) for peripheral selectivity for dopamine receptors. L-646,462 is, therefore, selective in vivo, preferentially blocking dopamine and 5-HT receptors located outside the blood-brain barrier. With regard to dopamine-receptors, L-646,462 was about equipotent and more selective than metoclopramide, while being less potent and less selective than domperidone. Unlike metoclopramide or domperidone, L-646,462 also possessed a reasonably potent 5-HT receptor antagonist effect in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
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Glucose and anoxia accelerate the photocount due to luminescence of Ehrlich Ascites cells. Adriamycin also has this effect if glucose is present. Comparison with a chemical standard combined with estimates of cellular and population transmittance yield a photon generation rate of at least 10 . s-1 . cell-1 in the presence of 10(-2) M glucose, and twice this with anoxic conditions or 10(-5) M adriamycin. Effects of adriamycin on Ehrlich Ascites cell respiration may depend on the presence of glucose.
The first reported case of an angiosarcoma apparently arising from the superior vena cava is presented. The patient, a 20-year-old white man, was treated by surgical excision and reconstruction with dacron grafts from the left and right brachiocephalic veins to the right atrium. This was followed by a course of mediastinal irradiation. The patient remained clinically disease-free at 24 months post-treatment. The patient had occasional occupational exposure to polyvinyl chloride.
NCA, the chloro analog of the potent dopamine agonist NPA is an irreversible ligand at dopamine receptors in mammalian brain. The chloroethyl analog of the recently described putative dopamine autoreceptor agonist 3-PPP, 3-PPP-C1, was evaluated for its potential use as an irreversible autoreceptor ligand. N-Chloroethylation of 3-PPP reduced the intrinsic affinity of the agonist seven-fold and, consequently, in contrast to NCA, it was found that 3-PPP-C1 was not a good irreversible ligand at dopamine receptors.
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Antidepressants and electroconvulsive shock therapy (ECS) have been reported to alter adenosine-sensitive adenylate cyclase responses in rat brain, suggesting an involvement of the purine in the mechanisms by which antidepressants and antidepressant therapy produce their clinical effects. Chronic (14-21 days, 10 mg/kg/day by Alzet minipump) treatment with desmethylimipramine (DMI) and mianserin, while producing changes in beta-adrenoceptor (DMI) and serotonin-2 (DMI and mianserin) radioligand binding similar to those reported in the literature, has no effect on adenosine A-1 radioligand binding.
The enantiomers of the putative dopamine autoreceptor agonist, TL-99 (6,7-dihydroxy-2-dimethylaminotetralin) were examined in a number of in vivo and in vitro test paradigms to further examine the reported autoreceptor selectivity of this compound. The (+)-isomer of the aminotetralin was more active as a dopamine agonist than either the racemate or the (-)-enantiomer. In addition to this dopaminergic activity, TL-99 was found to be a potent alpha 2-adrenoceptor agonist, this activity being more prominent in the (+)-isomer. The (-)-isomer, however, was a weak alpha 2/DA receptor agonist and unlike the (+)-enantiomer was devoid of activity in the D-1-selective carp retina adenylate cyclase assay. Pharmacological examination of the effects of TL-99 on mouse locomotor activity showed that the effects of the aminotetralin in this dopamine autoreceptor test system were antagonized by either the alpha 2-antagonist, yohimbine or by the dopamine antagonist, sulpiride. TL-99 also produced contralateral turning in 6-OHDA lesioned rats. It is concluded that the apparent dopamine autoreceptor selectivity of TL-99 as assessed by in vivo animal test systems may be due partially to its alpha 2-agonist activity. The sedation and consequent reduction in mouse locomotor activity and in turning in the rat as the dose level is increased undoubtedly occurs via alpha 2-agonist and dopamine autoreceptor activity and cannot be interpreted as selectivity for the dopamine autoreceptor.
Patients with symptomatic cholelithiasis who represent higher than normal surgical risks may be the most suitable candidates for medical dissolution of gallstones. Chenodeoxycholic acid was given to 97 patients in a dosage of 15 mg/kg of body weight per day for a period of two years. Complete gallstone dissolution occurred in 27 of 97 patients (28%). If dropouts are excluded then the success rate is 27 of 64 patients (42%). Diarrhea was a common but manageable side effect for most. Thirty-two percent of patients developed chemical liver test abnormality; however, in only 13% was the degree of abnormality sufficient to require temporary (3%) or permanent (10%) cessation of therapy. Although better chemotherapeutic agents are needed, chenodeoxycholic acid is a reasonable choice for patients with non-calcified cholelithiasis in a functioning gallbladder if the patient is a heightened surgical risk. Because of the prolonged treatment period and the possibility of hepatotoxicity this treatment program requires a substantial commitment on the part of both the patient and the physician.
The dependence of histone synthesis upon concurrent DNA synthesis has been studied in rat spermatogenic and brain tumor (RT489) cells, both in vivo and in vitro. The uptake of [3H]amino acids into histone was determined with and without inhibiting DNA synthesis with hydroxyurea (HU). HU reduced [14C]thymidine incorporation into DNA to less than 5% of control values in all cases without affecting the levels of total cellular protein synthesis, confirming the specificity of HU for inhibiting DNA synthesis. RT489 cells, grown either in culture or as a solid tumor, show no detectable histone synthesis when the concentrations of HU are sufficiently high. In the testis, no inhibition of synthesis of histones occurring during the meiotic prophase is observed in vivo or in vitro. These results provide further support for the model that a high degree of coupling of histone and DNA synthesis may occur only in proliferating, non-differentiating cell types and that both types of regulation can be observed both in in vivo and in vitro systems.
Adenosine by interaction with discrete extracellular recognition sites can modulate cyclic AMP formation and cell firing in the mammalian CNS. The effects of adenosine on cyclic AMP formation are mediated through two extracellular recognition sites: a high affinity (Kd = 10(-9) M) site designated A-1, activation of which results in an inhibition of adenylate cyclase activity and a lower affinity site (Kd = 10(-6) M) designated A-2, activation of which stimulates adenylate cyclase activity. Stable radiolabeled analogs of adenosine have been used to label A-1 receptors in mammalian brain. Adenosine and its stable analogs are potent inhibitors of neurotransmitter release. In addition to being phosphodiesterase inhibitors, the alkylxanthines are also adenosine antagonists, stimulating neurotransmitter release and increasing cell firing by antagonism of the effects of endogenous adenosine. These effects have been attributed to the presence of an inhibitory purinergic tone. Adenosine and related purines have been implicated in the mode of action of several centrally active drugs including anxiolytics, antidepressants and analgesics. Future progress in understanding the potential physiological role of adenosine in the mammalian CNS will depend on the availability of more potent and specific adenosine antagonists, ligands specific for the A-2 receptor, and a better understanding of the factors that regulate adenosine availability.
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Synthesis of several members of the 9-oxaergoline ring system is presented. Both the C/D cis and the C/D trans isomers of 4,6,6a,8,9,10a-hexahydro-7-ethyl-7H-indolo[3,4-gh] [1,4]benzoxazine were prepared, and the C/D trans isomer was resolved into its optical isomers. The enantiomer having the highest affinity for the [3H]apomorphine binding site, (-)-trans-6-ethyl-9-oxaergoline [(-)-6b], was shown to have the same absolute configuration as the natural ergolines, namely, 6aR, 10aR. In vivo and in vitro pharmacological evaluation shows these 9-oxaergolines to possess potent dopamine agonist properties.
Chloro- and methyl-substituted 10H-pyrazino[2,3-b][1,4]benzothiazines were prepared and their structures determined by 13C NMR and X-ray crystallographic analysis. Alkylation afforded the 10-[3-(dimethylamino)-1-propyl] derivatives, which were compared to chlorpromazine in receptor-binding assays, in vivo behavioral tests, and electrochemical oxidation studies. In this series, the 2-chloro compound, 4c, proved to be the most effective derivative in displacing [3H]siperone, [3H]apomorphine, and [3H]prazosin radioligands from binding sites, being approximately as potent as chlorpromazine in this respect. However, none of the 10H-pyrazino[2,3-b][1,4]benzothiazines of this study were as active as chlorpromazine in in vivo tests predictive of neuroleptic activity.