Basic and Clinical Pharmacology & Toxicology

Carlini, C. R.; Gomes, C.; Guimaraes, J. A.; Markus, R. P.; Sato, H.; Trolin, G.

doi: 10.1111/j.1600-0773.1984.tb01912.xpmid: 6144234

Abstract: Some pharmacological‐toxicological effects of canatoxin, a toxic protein purified from the seeds of Canavalia ensiformis have been studied in mice and rats. The most obvious effect, a lethal tonic convulsion, was generally produced 10–15 min. after intravenous injection of 2–3 mg/kg of the highly purified protein (mol. wt. 88,000). After intraperitoneal, intramuscular or subcutaneous administration the convulsion produced by the same toxin dosis occurred within 24 hours. A spinal transection at the midthoracic level did not abolish the convulsions of the hindlimbs while destruction of the medulla below this level completely blocked the convulsions of the hindlimbs. The convulsions of the head and forelimbs were unaffected by these surgical pre‐treatments. The toxic protein did neither affect the isolated skeletal muscle nor did it potentiate nerve impulse induced contractions. The convulsive effect of canatoxin was potentiated by reserpine and attenuated by phenobarbital, diazepam, methenesine and also by haloperidol and spiroperidol. The total concentration of brain and spinal cord neurotransmitters seemed to remain unchanged after subconvulsive and convulsive doses of canatoxin. In the conscious rat the toxic protein did not change the blood pressure except for a shortlasting hypertensive response observed immediately before the onset of the convulsions. The heart frequency was lowered at subconvulsive and convulsive dosis but no effect was seen on the frequency of the rat isolated right atria exposed to high doses of canatoxin. The body temperature was lowered by a convulsive dosis of the toxic protein. The purified toxin did not show any haemagglutinating property or haemolytic phospholipase A2‐like activity. The results strongly suggest a central nervous site for the action of canatoxin. However, if the effects are produced by the intact protein or not as well as its exact mode of action, remain unexplained.

Lake, Brian G.; Rijcken, W. Robert Pels; Gray, Tim J. B.; Foster, John R.; Gangolli, Sharat D.

doi: 10.1111/j.1600-0773.1984.tb01913.xpmid: 6720315

Abstract: The oral administration of di‐n‐octyl phthalate (DNOP), mono‐n‐octyl phthalate (MNOP), di‐(2‐ethylhexyl) phthalate (DEHP) and clofibrate to young male Sprague‐Dawley rats for 14 days resulted in liver enlargement. Morphological examination of liver sections from DEHP and clofibrate treated rats, but not from either DNOP or MNOP treated animals, revealed increased numbers of peroxisomes (microbodies). Both DEHP and clofibrate treatment markedly stimulated the activities of certain peroxisomal marker enzymes whereas DNOP and MNOP produced only marginal effects. Similarly both DEHP and clofibrate, but not DNOP or MNOP, increased microsomal cytochrome P‐450 content and markedly stimulated microsomal lauric acid hydroxylation activity. The results thus demonstrate that whilst the branched chain phthalate ester DEHP induced peroxisomal proliferation, the straight chain analogue DNOP and its metabolite MNOP were essentially inactive. In addition, DEHP treatment appeared to induce similar form(s) of cytochrome P‐450 in rat liver to those previously described after clofibrate administration.

Grabowska‐Andén, Maria; Andén, Nils‐Erik; Bárány, Ernst; Magnusson, Anneli

doi: 10.1111/j.1600-0773.1984.tb01914.xpmid: 6720316

Abstract: Conscious rats were given intracerebral injections by preplaced microsyringes. The injectates were 0.3–0.5 μl of 125I‐ and 131I‐o‐iodohippurate. One hour after injection the isotopes present in the unopened cranial cavity were measured by gamma spectrometry. Some animals received 200 mg/kg probenecid intraperitoneally and this reduced the rate of absorption from injectates into the corpus striatum to 65.7×12.6% of control; from injectates into the cerebellum to 57.1×9.8% of control. Dye injections showed that injections into the cerebellum did not remain in the parenchyma, in contrast to injections into the corpus striatum or thalamus. Probenecid was also given as 2.9% solution, pH 7, mixed with the iodohippurate in the microsyringe. It had no effect on injections into the cerebellum, reduced the rate of absorption from the corpus striatum to 80.9×3.2% of controls and that from the thalamus to 88.3×2.2%. The results indicate parenchymal probenecid‐sensitive transport of iodohippurate from the corpus striatum and thalamus but failed to settle the matter for the cerebellum.

Buch, Jan; Bundgaard, Allan

doi: 10.1111/j.1600-0773.1984.tb01915.xpmid: 6720317

Abstract: 8 stable asthmatics were at random given placebo, 0.125 mg, 0.25 mg, 0.5 mg and 1 mg terbutaline intramuscularly or 2.5 mg as inhalation. Systolic time intervals, echocardiographic parameters and peak expiratory flow (PEF) were measured. Maximal circulatory and respiratory response was obtained after 0.5 mg and 0.25 mg, respectively. The circulatory effect of 2.5 mg inhalated terbutaline equalled 0.125 mg given intramuscularly, while this dosage elicited maximal bronchodilator effect. Thus, nebulized terbutaline has only a minimal circulatory effect, and even the intramuscular dosages were without dramatic circulatory side effects.

Shinobu, Leslie A.; Jones, Shirley G.; Jones, Mark M.

doi: 10.1111/j.1600-0773.1984.tb01916.xpmid: 6720318

Abstract: The sodium and ammonium salts of N‐methyl‐D‐glucamine dithiocarbamate were prepared and their usefulness as antidotes for cadmium intoxication investigated. This chelating agent was found to be effective in both acute and repeated exposure cadmium poisoning. A single intraperitoneal injection of sodium N‐methyl‐D‐glucamine dithiocarbamate (NaNMG‐DTC), administered at a level greater than 1.1 mmol/kg body weight, protects against a normally lethal (>95%) dose of cadmium chloride (10 mg CdCl2/kg body weight) and results in a subsequent dose‐dependent decrease in the liver and kidney burdens of cadmium ion. In repeated exposure cadmium intoxication, repeated administration of NaNMG‐DTC can result in substantial reductions in both the kidney (71%) and the liver (40%) levels of cadmium. The LD50 of the compound was not determined, but single injections of 26.6 mmol/kg body weight (injectate volume 1.0 ml) are well tolerated in mice.

Grynne, Birthe H.; Maurset, Atle R.; Hobnen, Aase T.; Enger, Mette

doi: 10.1111/j.1600-0773.1984.tb01917.xpmid: 6144235

Abstract: In vitro μ and δ opioid receptor binding is known to be influenced by ions. High affinity 3H‐SKF10047 and 3H‐ethylketocyclazocine binding sites are found in brain membranes and postulated to be similar to μ opioid receptor binding. To investigate this postulate, we have studied how the high affinity binding of 3H‐SKF10047, 3H‐ethylketocyclazocine, a tritiated μ agonist, μ antagonist and δ agonist is altered when the radioreceptor binding assay incubation buffer is changed. The binding of 3H‐ethylketocyclazocine and the μ antagonist (3H‐naloxone) is highest in isotonic HEPES buffer, while the binding of the μ (3H‐dihydromorphine) and δ (3H‐D‐ala‐D‐leu‐enkephalin) agonist is highest in hypotonic Tris‐HCl buffer. 3H‐SKF10047 binding is similar in the two buffers. The inhibition of 3H‐ethylketocyclazocine, 3H‐SKF10047 and tritiated μ and δ opioid ligands by seven unlabeled ligands is then compared in the two buffers. Morphine chloride is a more potent inhibitor of 3H‐ethylketocyclazocine binding and tritiated μ ligand in hypotonic Tris‐HCl buffer than in isotonic HEPES buffer. The potency of naloxone, nalorphine, SKF10047, D‐ala‐D‐leu‐enkephalin, cyclazocine and phencyclidine in inhibiting 3H‐ethylketocyclazocine binding is independent of the buffer system. None of the seven unlabelled substances change potency with buffer change when inhibiting the 1.2 nM 3H‐SKF10047 binding. In sum our results show that 1 nM 3H‐ethylketocyclazocine binding is influenced by buffer change in a manner very similar to μ ligand binding, while the 1.2 nM 3H‐SKF10047 binding is only slightly influenced by buffer change and therefore different from μ ligand binding.

Grynne, Birthe H.; Bock, Elisabeth; Holmen, Aase T.; Slange, Kirsten

doi: 10.1111/j.1600-0773.1984.tb01918.xpmid: 6326467

Abstract: Rat synaptosomal plasma membranes were extracted with a detergent (CHAPS, a zwitterionic derivative of cholic acid), μ and δ opioid receptor binding and adenylate cyclase activities were tested in the intact membranes and in the supernatants from detergent treated membranes. The 6000 x g/8 min. supernatant contained μ receptor binding equal to 33% of the μ receptor binding measured in the untreated membranes. When the detergent treated membranes were sedimented at (50,000 x g/10 min.), 23% of the μ receptor binding was recovered in the supernatant. After a 100,000 x g/30 min. centrifugation the supernatant contained 10% of the μ receptor binding when compared to untreated membranes. Of the 5 receptor binding found in intact membranes, 10% or less was recovered in the 3 supernatants described above. Furthermore, the μ and δ receptor binding were distributed differently among particles in the supernatants. This indicates differences in the chemical properties of the μ and δ opioid receptors. Adenylate cyclase assays showed that the G/F site of this enzyme complex was inactivated in the supernatants from detergent treated membranes parallel to the δ receptor binding decrease. However, the catalytic part of adenylate cyclase was present in the supernatants and seemed resistant to the detergent.

Chandra, Satya V.; Murthy, R. C.; Husain, Tahir; Bansal, S. K.

doi: 10.1111/j.1600-0773.1984.tb01919.xpmid: 6326468

Abstract: The effect of interaction of Mn2+, Pb2+ and Cd2+ on (Na+‐K+) ATPase and uptake of labelled dopamine (3H‐DA) and labelled noradrenaline (3H‐NA) were studied in vitro in rat brain synaptosomes. The inhibition of (Na+‐K+) ATPase by Pb2+ and Cd2+ alone was concentration dependent, however, Mn2+ had almost no effect on the activity of this enzyme. Interaction of Cd2+ with either Pb2+ or Mn2+ was most powerful in inhibiting the activity of synaptosomal transport ATPase. Lower concentrations of Pb2+ increased while higher concentrations inhibited synaptosomal uptake of 3H‐DA and 3H‐NA. Lower concentrations of Cd2+ increased the uptake of 3H‐DA while at concentrations of 100 μM, the uptake was inhibited, this metal had strong inhibitory effect on the uptake of 3H‐NA. Mn2+ had inhibited the uptake of labelled amines. Interaction of Mn2+ with Pb2+ or Cd2+ produced inhibition on the uptake of 3H‐DA and 3H‐NA. The results of the uptake of biogenic amines in the presence of metal ions apparently had no correlation with the activity of (Na+‐K+) ATPase which is involved in the active transport of cations across cell membranes.

Kallama, Seija; Hemminki, Kari

doi: 10.1111/j.1600-0773.1984.tb01920.xpmid: 6720319

Abstract: Guanosine was reacted in vitro with phosphoramide mustard, chloromethine hydrochloride, and chlorambucil. The products were isolated by HPLC and characterized by UV and fluorescence spectroscopy, and C‐8 tritium exchange. The primary products were 7‐alkylguanosines according to such evidence. Phosphoramide mustard had 1/10 of the apparent alkylation activity of two other mustards. The primary 7‐alkylguanosines were unstable at pH 7.4 and 37°; t1/2 were 3 min. for chloromethine hydrochloride, 2.7 hrs for chlorambucil and 3.0 hrs for phosphoramide mustard. Both dechlorination at the unbound arm of the mustard and imidazole ring opening og guanosine appeared to account for such instability.

Elovaara, Eivor; Pfäffli, Pirkko; Savolainen, H.

doi: 10.1111/j.1600-0773.1984.tb01921.xpmid: 6609523

Abstract: Adult male rats exposed to tetrahydrofuran vapour at 8.2 (200 p.p.m.), 41 (1,000 p.p.m.) or 82 μmol/1 (2,000 p.p.m.) for 2 to 18 weeks, five days a week, 6 hrs daily, showed dose‐dependent brain and perirenal fat solvent burden linearly correlated to each other. After two weeks of exposure, the body burden of tetrahydrofuran seems to decrease. This might have been caused by increased oxidative metabolism as enhanced 7‐ethoxycoumarin O‐deethylase activity was detected in liver and kidneys in the 2nd week and onwards. The exposure also caused inhibition of alcohol and formaldehyde dehydrogenase activities in liver at the highest dose. Biochemical effects in the cerebellum were not detected while gluteal muscle specimens showed increased succinate dehydrogenase activity in a dose‐related manner. This points to effects on the energy metabolism. Muscle acetylcholine esterase activity was also increased showing possible effects on the myoneural junctions.