Phencyclidine and psychotomimetic sigma opiates: recent insights into their biochemical and physiological sites of action.
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Benzomorphans↗
Biomedical subjects
E Weber
Publications and source records attributed to E Weber.
Measurement of the analgesic effects of aspirin with a new experimental algesimetric procedure.
Using controlled long lasting noxious squeeze stimuli applied to the interdigital webs we have tried to develop experimental methods allowing us to measure the effects of peripherally acting analgesics. In the present double-blind cross-over study with 12 subjects we tested the effects of aspirin (1000 and 1500 mg) vs. placebo on subjective pain induced by alternately applied 12 N (Newton) and 8 N stimuli. During the sessions blood samples were taken in regular intervals to measure acetylsalicylate (ASA)- and salicylate (SA)-plasma levels. Analyses of variance were computed with several psychophysical parameters. Both the '12 N' and the '8 N' ratings discriminated between placebo and aspirin, however, only the ratings obtained from the stronger stimuli discriminated between two doses of aspirin. Subsequently we computed analyses of covariance with the ASA- and SA-plasma levels as covariates. Significant (negative) correlations of pain ratings and SA-plasma levels were found for the high dose of aspirin, but there were no significant correlations of ASA levels and ratings.
Analgesia↗
Autoradiographic visualization of haloperidol-sensitive sigma receptors in guinea-pig brain.
The distribution of sigma receptors in guinea-pig brain is demonstrated using quantitative autoradiography and the new selective sigma receptor probe, 1,3-di(2[5-(3)H]tolyl)guanidine. Pharmacological analysis, using slide-mounted brain sections, reveals that this site is saturable and has a drug-specificity profile similar to that found in homogenate binding studies. Autoradiography reveals a moderate to high density of discrete, specific labeling superimposed on a lower level of homogeneous 1,3-di(2[5-(3)H]tolyl)guanidine binding. Both patterns are displaced by incubation with 10 microM haloperidol or 1,3-di-ortho-tolyl-guanidine. In the forebrain, the highest density of binding is associated with the magnocellular-neuroendocrine and limbic systems; lower densities are distributed in non-limbic nuclei and the lowest levels occur in the extrapyramidal system. In the midbrain and hindbrain, motor nuclei involved in voluntary and involuntary motor behavior are discretely labeled, as are many of the cranial nerve nuclei. The anatomical distribution of the haloperidol-sensitive sigma receptors is distinct from the pattern of phencyclidine receptors and suggests sigma compounds may effect endocrine, emotional and motor behavior.
Animals↗
Identification of the binding subunit of the sigma-type opiate receptor by photoaffinity labeling with 1-(4-azido-2-methyl[6-3H]phenyl)-3-(2-methyl[4,6-3H]phenyl)guanidine.
The sigma-type opiate receptor is a distinct binding site in the brain that may mediate some of the psychotomimetic effects caused by benzomorphan opiates and phencyclidine in humans. We have developed a synthetic, highly selective ligand for this receptor, 1,3-di-o-tolylguanidine (DTG). To identify the binding protein(s) of the sigma receptor, we have now synthesized a radiolabeled azide derivative of DTG, 1-(4-azido-2-methyl[6-3H]phenyl)-3-(2-methyl[4,6-3H]phenyl)-guanidine ([3H]N3DTG). In guinea pig brain membrane binding assays conducted in the dark, [3H]N3DTG bound reversibly, selectively, and with high affinity (Kd = 10 nM) to sigma receptors. The drug specificity profile of reversible [3H]-N3DTG binding was identical to that of [3H]DTG and 3H-labeled (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding indicating that [3H]N3DTG is a selective sigma receptor ligand. Guinea pig brain membranes were photoaffinity-labeled with [3H]N3DTG. NaDodSO4/PAGE of detergent-solubilized membrane extract identified a single 29-kDa radioactive band. Sepharose Cl-6B gel chromatography of photolabeled brain membranes solubilized with the nondenaturing detergent sodium cholate showed a radioactive complex with a Stoke's radius of 4.6 nm (Mr, 150,000) that may represent the intact sigma receptor complex. NaDodSO4/PAGE of this complex showed that the radiolabeled material was a 29-kDa polypeptide that may be the binding subunit of the sigma receptor. The specific sigma receptor photoaffinity ligand described here should be a useful tool for purifying and characterizing the sigma receptor.
Affinity Labels↗
Dehydroepiandrosterone induced alterations in rat liver carbohydrate metabolism.
Long-term dietary administration of the adrenal hormone dehydroepiandrosterone (DHEA) to male Sprague-Dawley rats induced significant alterations in the activities of enzymes involved in liver carbohydrate metabolism. Although glycogen synthase activity was increased and phosphorylase decreased, glycogen stores were reduced. This was presumably related to lysosomal glycogen degradation, since alpha-glucosidase was increased. All rate-limiting enzymes of glucose metabolism which were studied (glucose-6-phosphate dehydrogenase, total hexokinases, pyruvate kinase, fructose-1,6-bisphosphatase) revealed markedly reduced activity, only glucose-6-phosphatase activity was increased. These enzymatic changes point to a far-reaching metabolic shift towards energy loss via decreased glucose consumption and increased glucose output. The enzyme pattern induced by DHEA is in many respects opposite to that induced in preneoplastic and neoplastic liver lesions by chemical hepatocarcinogens.
Animals↗
Enzyme histochemical and morphological phenotype of amphophilic foci and amphophilic/tigroid cell adenomas in rat liver after combined treatment with dehydroepiandrosterone and N-nitrosomorpholine.
Male Sprague-Dawley rats were investigated after N-nitrosomorpholine (NNM) treatment with concomitant and subsequent administration of dehydroepiandrosterone (DHEA) for development of pre-neoplastic and neoplastic liver lesions. In addition to clear, acidophilic, mixed cell and basophilic foci, a hitherto undescribed lesion type demonstrating a unique morphological and histochemical phenotype was observed in animals receiving both NNM and DHEA. The cells of the majority of these lesions for which we propose the designation amphophilic foci were characterized by increased granular acidophilia and randomly scattered cytoplasmic basophilia. Histochemically, reduced glycogen content and elevated activity of glucose-6-phosphate dehydrogenase (G6PDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), acid phosphatase (AP), succinate dehydrogenase (SDH) and catalase (CAT) were evident. The lack of gamma-glutamyl transpeptidase (GGT) or glutathione S-transferase placental form (GST-P) in foci of this type allowed clear differentiation from other NNM-induced focal lesions while suggesting certain similarities to pre-neoplastic cells induced by hypolipidemic agents. Similar enzyme histochemical patterns were characteristic for foci and later appearing nodules (adenomas) composed of amphophilic/tigroid cells the basophilic material of which was increased and frequently arranged in long striped bands. DHEA treatment, while not itself inducing any preneoplastic foci, was thus associated with altered phenotypic expression of foci and adenomas generated by NNM.
Animals↗
Phenotypic modulation of hepatocarcinogenesis and reduction in N-nitrosomorpholine-induced hemangiosarcoma and adrenal lesion development in Sprague-Dawley rats by dehydroepiandrosterone.
Dietary administration of 0.25% dehydroepiandrosterone (DHEA) during and subsequent to 7 weeks treatment with N-nitrosomorpholine (NNM) resulted in significantly reduced development of adrenal cortical lesions and hemangiosarcomas in the liver. In addition, distinct phenotypic modulation of hepatocellular tumours was observed after combined hormone and carcinogen treatment. Thus the neoplasms were characterized by a higher degree of differentiation, lower mitotic rate and reduced potential for metastasis as compared to tumours observed after NNM alone. The data clearly indicate that DHEA exerts an inhibitory effect on both adrenal and hepatocarcinogenesis similar to that earlier reported for neoplasia in lung, thyroid, colon and skin.
Adenoma↗
Sex-dependent, tissue-specific opposing effects of dehydroepiandrosterone on initiation and modulation stages of liver and lung carcinogenesis induced by dihydroxy-di-n-propylnitrosamine in F344 rats.
Administration of the hormone dehydroepiandrosterone (DHEA) (0.6% in the diet) during or subsequent to injections of the carcinogen dihydroxy-di-n-propylnitrosamine (DHPN) (2 X 1000 mg/kg body weight, i.p.) brought about alteration in the yield of preneoplastic lesions in liver and lung of both male and female F344 rats. Concomitant treatment with DHEA was associated with decrease in the numbers and size of glutathione S-transferase (GST-P)-positive hepatocellular foci while effecting a significant increase in development of lung lesions, especially in females. Long-term treatment with the hormone subsequent to carcinogen exposure brought about a reduction in numbers of liver foci in both sexes but in males was also associated with the development of large GST-P-negative foci and nodules of amphophilic/tigroid cell character. DHEA itself did not induce any focal lesions in the lungs or livers of either sex. Thus the hormone increased sensitivity to 'initiation' in the lung while decreasing that in the liver and exerted a sex-dependent pronounced modulation of the phenotype of a proportion of hepatocellular lesions.
Animals↗
Biochemical mechanisms of oxfenicine cardiotoxicity.
Oxfenicine (S-4-OH-phenyl-glycine) was proposed as a compound which would stimulate carbohydrate utilization in the heart and thus reduce oxygen requirement, especially in ischemic heart disease. Oral administration to rats for several weeks gave rise to an increase in heart, liver and kidney weights. The drug damaged mitochondrial metabolism, reducing oxygen consumption and uncoupling oxidative phosphorylation in all three organs. In heart mitochondria creatine phosphate kinase was inhibited and the creatine content of the mitochondria increased. Myocyte membrane functions (Ca uptake as well as Na/K-, Mg- and Ca-ATPases) were inhibited. In all three organs lipids (phospholipids and triglycerides) as well as free fatty acids showed a transient accumulation.
Adenosine Triphosphatases↗
Left ventricular function in mild hypertension after adrenergic blockade.
We previously used the Doppler transmitral flow velocity ratio A/E (A = late ventricular filling peak velocity; E = early ventricular filling peak velocity) and the age-adjusted ratio A/E/Age to detect left ventricular filling abnormalities in untreated mild hypertension. This study is a double-blind assessment of the effect of combined alpha- and beta-blockade (labetalol) and beta-blockade alone (atenolol) on left ventricular filling in mild hypertension. Twenty-seven patients blindly randomized to labetalol (12 patients) and atenolol (15 patients) treatment completed the echocardiographic and Doppler studies. Clinical and echo-Doppler data obtained at baseline and 6 weeks after initiation of therapy showed no difference between the two groups for age (49 +/- 10 vs 46 +/- 10 years), mean blood pressure (before therapy, 118 +/- 9 vs 117 +/- 8 mm Hg; after therapy, 108 +/- 12 mm Hg), left ventricular dimensions, wall thickness, systolic function, and mean late filling velocity A. There was no significant change in left ventricular mass and mass index with labetalol (left ventricular mass, 211 +/- 36 vs 216 +/- 38; mass index, 110 +/- 17 vs 112 +/- 16) or atenolol (245 +/- 41 vs 271 +/- 65; 120 +/- 18 vs 130 +/- 35). The mean velocity E, A/E, and A/E/Age ratios significantly improved with labetalol (p less than 0.05) but did not change significantly with atenolol. The improvement in A/E and A/E/Age ratios was primarily due to an increase in early filling velocity E.(ABSTRACT TRUNCATED AT 250 WORDS)
Atenolol↗
Endothelium-dependent responses in carotid and renal arteries of normotensive and hypertensive rats.
Endothelium-dependent relaxations are impaired in the aorta of various models of hypertension, but no data are available regarding the cerebral or renal circulation. Endothelium-dependent relaxations were studied in the carotid and renal artery of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Rings with and without endothelium were suspended in organ chambers for isometric tension recording. Acetylcholine and adenosine 5'-diphosphate (ADP) caused endothelium-dependent relaxations in both arteries that were impaired in the carotid, but not in the renal artery, of the SHR, similar to those to the endothelium-independent vasodilator sodium nitroprusside. Indomethacin did not affect relaxations to acetylcholine in the carotid artery, but it significantly augmented them in the renal artery. This finding suggests that an impaired vascular responsiveness to endothelium-derived relaxing factor is responsible for the decreased relaxations in the carotid artery of the SHR. In the renal artery, acetylcholine appears to release both endothelium-derived relaxing factor and a vasoconstrictor prostanoid. Carotid arteries of SHR were more sensitive to the constrictor effects of serotonin than were those of WKY. Endothelium removal caused a twofold to eightfold increase in sensitivity to serotonin in both strains. Thus, endothelium-dependent relaxations to acetylcholine and ADP are reduced and constrictions to serotonin are enhanced in the carotid, but not in the renal, artery of the SHR.
Acetylcholine↗
Reduction of pinocytotic vesicle surface density in cultured bovine aortic endothelial cells. A quantitative ultrastructural freeze-etching study.
The development of culture techniques for endothelium of the large vessels has stimulated many studies to understand endothelial functions in normal and pathological conditions. In this report we describe that in primary cultures the mean surface density of pinocytotic vesicles, evaluated by computerized morphometric analysis of endothelial cell plasma-membrane, dramatically decreases with respect to that of the cells immediately detached from the arterial wall (6.7 +/- 1.1 microns2 against 19.5 +/- 2.2 microns2, p less than 0.001). The results are unchanged if the cells are enzymatically or mechanically detached from the vessel wall or from the culture flask. After the first passage, the mean surface density of pinocytotic vesicles decreases further (2.5 +/- 1.3 microns2 p less than 0.01). After the 2nd and the 3rd passages, the morphometrical values of endothelial cell plasma-membrane remain low (1.5 +/- 0.2 microns2; 2.5 +/- 0.2 microns2). When endothelial cultures are employed to study pathological aspects of disease, not only the aging process but also the possible occurrence of early changes have to be taken into consideration.
Animals↗
[Compliance: a new monitoring method with the Medication Event Monitoring System].
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Drug Packaging↗
Non specific acid esterase activity in human periapical inflammatory cells.
The fine structural localization of non specific acid alpha-naphthyl acetate esterase activity (ANAE) in human periapical inflammatory cells was studied in sections of paraffin embedded tissue of 20 human periapical lesions (granulomas). Examination of specimens incubated with ANAE resulted in ANAE+ cells interpreted as T-lymphocytes, monocytes, macrophages, giant cells and plasma cells. ANAE- lymphocytes were interpreted as B cells. Our findings do not seem to confirm the presence among human periapical inflammatory cells of NK (natural killer) cells. T-lymphocytes were the most represented cellular type. The macrophages with ANAE+ reaction were numerous in all specimens observed and the variation in staining intensity could reflect a varying stage of activation. These findings allow conclusions about the role of T-lymphocyte mediated immune reaction in the pathogenesis of periapical lesions. The possibility that the activated T-lymphocytes within the periapical lesions may have a critical role in establishing and maintaining granuloma formation is also discussed.
Carboxylesterase↗
Expression of opioid peptides in tumors.
We looked for opioid peptides and their precursors in 108 tumors of both neuroendocrine and nonneuroendocrine origin, using a monoclonal "pan-opioid" antibody, 3-E7, which recognizes the tetrapeptide Tyr-Gly-Gly-Phe (the sequence responsible for pharmacologic activity in all known opioid peptides), in conjunction with polyclonal antibodies directed against representative peptides of each of the three precursors (alpha-endorphin, [met]enkephalin-Arg-Gly-Leu, and dynorphin B). Using the avidin-biotin immunoperoxidase technique, we observed consistent cytoplasmic immunoreactivity (at least focally) in all of 15 adrenal pheochromocytomas, all of 6 thyroid medullary carcinomas, and all of 5 pituitary adenomas. Opioid staining was also observed in parathyroid adenomas (8 of 9), pancreatic islet-cell tumors (7 of 10), carcinoid tumors from various sites (18 of 26), and paragangliomas (1 of 2). There was no immunoreactivity in pulmonary small-cell carcinomas, Merkel-cell tumors of skin, neuroblastomas, or any of the non-neuroendocrine tumors examined. The expression of alpha-endorphin, [met]enkephalin-Arg-Gly-Leu, and dynorphin B varied from tumor to tumor; however, positive staining with the "pan-opioid" antibody was found in each tumor containing at least one of the three precursors. Opioid peptide immunoreactivity was also detected in non-neoplastic cells of the adrenal medulla, pancreatic islets, pituitary, intestinal and bronchial mucosa, and intestinal myenteric plexuses. We conclude that opioid expression within tumors is most likely due to enhanced expression of a normal cell product and that opioid peptides are useful markers of neuroendocrine differentiation in many tumors.
Antibodies, Monoclonal↗
Synthesis and characterization of an affinity label for brain receptors to psychotomimetic benzomorphans: differentiation of sigma-type and phencyclidine receptors.
Brain sigma-type receptors and phencyclidine receptors are thought to mediate the psychotomimetic effects of benzomorphans and phencyclidine in humans. Recently, we reported the characterization of a selective sigma receptor ligand, 1,3-di-o-tolyl-guanidine (DTG), that shows negligible crossreactivity with phencyclidine receptors. Here we describe the synthesis and characterization of an isothiocyanate derivative of DTG, di-o-tolyl-guanidine-isothiocyanate (DIGIT). Guinea pig brain membranes treated with nanomolar doses of DIGIT followed by extensive washing exhibit a dose dependent reduction of [3H]DTG and (+)[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [+)[3H]3-PPP) binding to sigma receptors. Binding of radiolabelled ligands for phencyclidine, mu-opioid, benzodiazepine and dopamine-D2 receptors is not affected by membrane treatment with DIGIT, indicating specificity of the affinity label for sigma-type receptors. Treatment of DIGIT-derivatized membranes with 2 M NaCl does not result in recovery of sigma binding activity, suggesting that DIGIT's interaction with sigma receptors is not of an ionic nature. Equilibrium saturation binding experiments show that the inhibition of [3H]DTG binding to sigma receptors by DIGIT pretreatment of membranes is attributable to an irreversible reduction in the affinity (increase in Kd) of sigma receptors for DTG. The finding that sigma receptors are irreversibly modified by DIGIT whereas phencyclidine receptors are not affected suggests that sigma receptors are physically separate from phencyclidine receptors. The availability of a selective affinity label for the sigma receptor should facilitate the purification of the receptors and the characterization of sigma-type pharmacological effects in vivo and in vitro.
Affinity Labels↗
Both the sigma receptor-specific ligand (+)3-PPP and the PCP receptor-specific ligand TCP act in the mouse vas deferens via augmentation of electrically evoked norepinephrine release.
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Animals↗
Clinical and practitioners' reports on adverse effects of co-trimoxazole.
This study concerns the incidence of side effects occurring in connection with the prescription of co-trimoxazole which, according to the observations of medical practitioners, were suspected of being drug related. It is based on reports from 260 doctors in the Nordbaden/Rheinlandpfalz area between 1981 and 1984, as well as on those from hospital doctors concerning 33,300 in-patients at the Department of Internal Medicine at the University Hospital of Heidelberg from 1980 to 1983. General practitioners' reports: Of 3,739 side effects reported over a three and a half year period, 180 were related to drugs containing co-trimoxazole. Side effects were 3.3 times as frequent with the "forte" dosage as compared to the 80 mg trimethoprim/400 mg sulfamethoxazole preparation. The most frequently cited unwanted reactions concerned the skin (n = 63, of which two were Quincke oedema and three were urticarious reactions) and the gastrointestinal tract (n = 52), as well as disturbance of well being (n = 30). Gastro-intestinal disturbances appeared to occur more frequently after a higher than after a lower dosage. Clinicians' reports: During the period of observation an average of 12.6% of all in-patients were treated with drugs containing co-trimoxazole. The total number of cases of side effects due to this drug amounted to 255. Serious reactions included: two anaphylactic reactions; two thrombocytopenias below 80,000/mm3; and two cases of Lyell's syndrome (one of which could not be confirmed beyond all doubt). Side effects occurred more often after i.v. than after oral application.(ABSTRACT TRUNCATED AT 250 WORDS)
Anti-Infective Agents↗