Analgesia induced by brief footshock is inhibited by 5-hydroxytryptamine but unaffected by antagonists of 5-hydroxytryptamine or by naloxone

Exposure to footshock (1 mA) for 30 sec induced a marked analgesia that was enhanced by pretreatment with the 5HT synthesis inhibitor, p-chlorophenylalanine, and attenuated by the 5HT releasing drugs p-chloroamphetamine and fenfluramine, by the 5HT re-uptake inhibitor, fluoxetine and by the 5HT agonists, 5-methoxy-N,N-dimethyltryptamine and MK212. However, agonists, quipazine and trifluoromethylphenylpiperazine, with greated reported affinities for 5HT binding sites on rat brain membranes than MK212 were without effect as were the antagonists metergoline, methysergide, cyproheptadine, mianserine and methiothepin. The specific opioid antagonist naloxone was also without effect. The results in general indicate that analgesia induced by brief footshock (1 mA, 30 sec) is inversely related to 5HT availability but thereis little evidence of involvement of known 5HT receptors.     

Synergism by caffeine and by cocaine of the motor control deficit produced by midazolam

To evaluate the effects of caffeine and cocaine on the impairment of discriminative motor control produced by midazolam, rats were trained to hold a force transducer operated with a paw so that it remained between upper and lower limits of a force band for a continuous 1.5-s period to deliver each food pellet. Acute doses of 3 mg/kg midazolam SC impaired motor performance. Except for one animal, caffeine (10-40 mg/kg IP) had little or no effect on performance, while cocaine (3.75-22.5 mg/kg IP) produced dose-related impairment. When each dose of caffeine was combined with 3 mg/kg midazolam, a marked synergism in motor performance impairment occurred. Cocaine plus midazolam produced mainly an additive synergism. The conspicuous synergistic action of caffeine on the motor control deficit produced by midazolam contrasts with the typical antagonism found between the benzodiazepines and methylxanthines when performance is evaluated by psychomotor tests not requiring fine motor control.     

Deamination of beta-phenylethylamine by monoamine oxidase--inhibition by imipramine

The oxidative deamination of tyramine (Tyr), 5-hydroxytryptamine (5-HT), and β-phenylethylamine (PEA) by mitochondrial preparations of rabbit lung and brain was inhibited by imipramine. This tricyclic iminodibenzyl antidepressant drug was most effective in decreasing the deamination of PEA: at 1 × 10^?4M imipramine, deamination of PEA, Tyr and 5-HT was inhibited by approximately 70, 45 and 45 per cent, respectively, when either lung or brain mitochondrial monoamine oxidase (MAO) preparations were used. Imipramine-induced inhibition of MAO was shown to be of a mixed type based on Lineweaver-Burk plots, but was found to be completely reversible. The desmcthyl and didesmethyl derivatives of imipramine were equally as effective as the parent drug in inhibiting the deamination of PEA, whereas the N-oxide analog of imipramine was less effective as an inhibitor of this reaction. These results support the premise that the action of imipramine as a clinically effective antidepressive agent may be related to its inhibitory effect on the specific form of MAO which deaminates PEA.     

Augmentation by serrapeptase of tissue permeation by cefotiam

Cefotiam (CTM) is a new cephalosporin with a broad spectrum of activity against both Gram-positive and Gram-negative microorganisms. Cephalosporins are widely used for prophylaxis of infections in patients undergoing thoracotomy. Augmentation by serrapeptase on tissue permeation of CTM was examined in 35 thoracotomy patients with lung cancer. The subjects were divided into two groups according to the method of the administration of CTM. Group I consisted of 17 subjects, each of whom received a single dose of 2 g of CTM alone by an instillation for 30 minutes. Group II consisted of 18 subjects, each of whom received a combination of CTM and serrapeptase; serrapeptase was given 2 tablets (10 mg) each time for three times/day until the day before surgery, and then CTM was administered by the same procedure. The following results were obtained: Individual difference was observed for the permeation of CTM into tissues. Pathologic differences also affected the permeation. Nevertheless, the CTM levels in pulmonary tissues reached about a half of those in the blood in both the single dose group and the combination group, hence sufficient concentrations exceeding MIC80 for main microorganisms that caused infections in the lung were obtained. The concentrations of CTM in inflammatory tissues have showed lower levels than those of normal tissues in both CTM single dose and the combination groups. Decrease of blood flow volume may have contributed to the reduction in levels of CTM in the inflammatory tissues. The ratio of the concentration of the drug in pulmonary tissues to that in the blood was 29.1 +/- 2.5% in the single dose group, and 44.2 +/- 6.0% in the combination group, the latter showing quite a significant increase (P less than 0.05). Combined administrations of CTM and serrapeptase deserves more trials in the case when surgical treatments of the lung are performed. An antiinflammatory effect of serrapeptase in the respiratory system is expected, and in addition, the combined use of CTM and serrapeptase should stimulate permeation of the antibiotic into tissues.     

Immunomodulation by non-absorbable antibiotics given by the intragastric route

To test the role of bacterial fractions released from intestinal flora during immunomodulation by antimicrobial agents, BALB/c mice were treated with the non-absorbable antibiotics polymyxin B or teicoplanin by the intragastric route. The composition of faecal microbiota and the capacity of spleen cells to proliferate in response to B-cell and T-cell mitogens were assessed at several times during the treatment. Both antibiotics lowered the count of some bacteria of the intestinal flora and induced significant modifications in spleen cell ability to proliferate in response to mitogens. Thus, the active fractions released from intestinal bacteria during antibiotic treatments may be able to induce immunomodulating effects.     

Interference by cephalosporins with creatinine measurement by desk-top analyzers

Summary We have carried out a study to evaluate the interference by cephalosporins with the measurement of creatinine by desk-top analyzers. The cephalosporins evaluated at concentrations of 0–250 mg/l were cefazolin sodium, cefoxitin sodium, cefotaxime sodium, and ceftazidime pentahydrate. The instruments evaluated were DT60 (Kodak, Rochester, USA), Seralyzer (Ames Division, Miles Laboratories, IN, USA), and Vision (Abbott Labs, Chicago, USA). All studies were done in plasma.None of the cephalosporins showed any interference with the DT60 analyzer. With the Vision and Seralyzer no interference was seen with cefotaxime or cefazolin. With cefazolin an increase of 10–20 µmol/l creatinine was seen for every 20 mg/l of drug; with cefoxitin there was an increase of 50–80 µmol/l of creatinine for every 100 mg/l of drug.Erroneous creatinine values may be found in patients taking cefazolin and cefoxitin and may lead to inappropriate clinical management.     

Bacteriolysis is inhibited by hydrogen peroxide and by proteases

Treatment of Staphylococcus aureus in vitro with cationic agents results in the activation of their autolytic wall enzymes and in the degradation of their cell walls. Exposure of staphylococci either to hydrogen peroxide or the proteinases abolished the autolytic process. This effect was totally reversed by catalase and by proteinase inhibitors, respectively. It is suggested that the failure of neutrophils and macrophages to effectively degrade microbial cell wall components in inflammatory sites might be due to the inactivation of the autolytic wall enzymes of bacteria by hydrogen peroxide and by proteinases generated by the activated leukocytes. This might explain the prolonged chronic inflammatory sequelae seen following infections.     

Antagonism of morphine by beta-melanocyte-stimulating hormone and by tetracosactin

Using the decerebrate—spinal Lloyd preparation morphine depressed evoked mono- and polysynaptic reflex activity, β-melanocyte-stimulating hormone enhanced monosynaptic reflex activity, and tetracosactin had no effect. When morphine injection was preceded either by β-melanocyte-stimulating hormone or by tetracosactin a statistically significant depression was not observed. The stimulant actions of β-melanocyte-stimulating hormone did not appear to account for its capacity to antagonize morphine. The fall of blood pressure which follows the administration of morphine in this preparation was not antagonized by the prior administration of either polypeptide.     

Bronchial smooth muscle responses evoked by toluene diisocyanate are inhibited by ruthenium red and by indomethacin.

We have investigated the ability of ruthenium red, an inorganic dye with Ca2+ entry-blocking properties and a selective antagonist of capsaicin, and of indomethacin, a cyclooxygenase inhibitor, to inhibit bronchial smooth muscle responses evoked by toluene diisocyanate in guinea pigs. Previous exposure of isolated guinea pig bronchi to ruthenium red significantly decreased the response produced by toluene diisocyanate. Further, the response to toluene diisocyanate was significantly decreased by pretreatment with indomethacin. These findings provide evidence that toluene diisocyanate-induced contractions of guinea pig bronchi are produced indirectly by generation of a prostanoid that activates capsaicin-sensitive afferents via a ruthenium red-sensitive mechanism.     

Hypoalgesia induced by counter-irritation is not affected by pCPA pretreatment

In a previous work (4), it has been described that a noxious visceral stimulation through the intraperitoneal injection of acetic acid (ipAA) induced a transient and low magnitude increase in tail-flick latencies, but a marked increase in the threshold for vocalization and hot-plate latencies. In the present work, this phenomenon of hypoalgesia through counter-irritation was investigated in intact rats with or without pretreatment with the potent serotonin depletor parachlorophenylalanine (pCPA). Three behavioural tests were performed. In two tests (tail flick, vocalization induced by transcutaneous electrical stimulation of the tail), pCPA pretreatment induced an increase of baseline levels, before IP injection of the allogenic agent (ipAA). In the third test, pCPA pretreatment had no effects on jump latencies. Parachlorophenylalanine pretreatment had no effect upon hypoalgesic actions of IP injected AA in all three tests. These results are discussed in terms of pCPA's differential effects upon basal nociception and analgesia induced by various heterotopic nociceptive stimulations.     

Carcinogenesis in rats by substituted dialkylnitrosamines given by gavage.

A number of nitrosamines that have been studied by administration to rats as solutions in drinking water have been examined by gavage administration of similar doses, for assessment of the role of pharmacokinetics in organ-specific carcinogenesis. Methylnitrosoethylamine was more effective as a liver carcinogen by gavage than in drinking water and gave rise to tumors of the lung and nasal mucosa by the former route, but not the latter. By gavage, methylnitroso-2-oxopropylamine and methylnitroso-2-hydroxypropylamine induced mainly tumors of the esophagus, as they did when given to rats in drinking water, but the potency was greater by gavage. At a higher dose rate (85 micromoles per week) methylnitrosohydroxypropylamine induced a high incidence of mesenchymal tumors of the kidney and lung tumors, in addition to esophageal tumors, but methylnitrosooxopropylamine did not. The tobacco-specific carcinogen NNK induced tumors of the liver, and to a lesser extent, of the lung and nasal mucosa when given by gavage to rats, as it did by other routes of administration. The similarly basic nitrosamine methylnitroso-N, N-dimethylaminoethylamine was equally potent, whether administered by gavage or in drinking water to rats, and gave rise only to tumors of the esophagus. The cyclic nitrosamine nitrosomorpholine was equally effective by gavage and in drinking water, but induced in rats more esophageal tumors by gavage in addition to a high incidence of liver tumors. Its 2-hydroxy derivative, a postulated metabolic intermediate of nitrosodiethanolamine, was a very much weaker carcinogen than either the latter or nitrosomorpholine, and induced low incidences of liver and lung tumors toward the end of the lifespan of the rats.     

Local injuries by accidental ingestion of corrosive substances by children

Own data and analysis of previous publications show that situations where accidental ingestion of corrosive substances by children may have happened are frequent, but severe corrosive esophagitis leading to perforation or stricture formation is very rare. In case of suspected esophageal injury, esophagoscopy and glucocorticoid treatment become necessary. The evaluation of the initial symptoms in patients from our own material and from the literature indicates that all children with serious esophageal burns had one or more of the following symptoms: visible burns in the oral cavity, hypersalivation, retching, vomiting, retrosternal or epigastric pain, cardiovascular collaps, airway stenosis. Hence, children with an uncertain history of ingestion and without any of these symptoms need not be treated. After ingestion of liquid substances, but never of dry or granular products, lesions in the esophagus without accompanying burns in the oral cavity were observed. The evaluation of 1158 cases of accidental ingestions of several types of household products and a collection of data from the literature on the causticity of these substances shows that cleaners containing mainly detergents and phosphates (with pH values generally between 9 and 11), and household bleaches on sodium hypochlorite basis are relatively harmless. Drain cleaners (NaOH), decalcifiers (formic acid) and detergents for automatic dish washing machines (metasilicates) are very caustic and are responsible for the majority of serious accidents in children.

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Zusammenfassung Eigenes Zahlenmaterial und eine Durchsicht früherer Veröffentlichungen ergeben, daß Situationen, in denen Kinder versehentlich ätzende Haushaltsmittel zu sich genommen haben (oder haben könnten), häufig sind, daß aber schwere Ösophagusverätzungen mit Perforationen oder Strikturbildung im Kindesalter sehr selten sind. Beim Verdacht auf eine erheblichere Ösophagusverätzung werden Ösophagoskopie und Glukokortikosteroidbehandlung erforderlich. Alle Kinder mit erheblichen Ösophagusverätzungen, über deren Aufnahmestatus in unseren Unterlagen oder in Publikationen Angaben gemacht worden sind, hatten mindestens eines der folgenden Symptome: sichtbare Ätzspuren in Mund und Rachen, Hypersalivation, Würgen, Erbrechen, Schmerzen hinter dem Brustbein oder im Oberbauch, Kreislaufkollaps, Luftwegsstenose. Demnach brauchen Kinder, deren Anamnese nur fraglich ist, und die keines der genannten Symptome haben, nicht behandelt zu werden. Bei trockenen Substanzen waren stets Ätzspuren in der Mundhöhle sichtbar, wenn es zu Ösophagusverätzungen gekommen war; bei Ösophagusschäden durch Flüssigkeiten fehlen gelegentlich Nekrosen in der Mundhöhle. Die Auswertung von 1158 Verätzungsunfällen bei Kindern mit verschiedenen Haushaltsprodukten, und eine Zusammenstellung bereits bekannter, relevanter Daten zeigt, daß Allzweckreiniger auf Detergentien- und Polyphosphat-Basis (in der Regel mit pH-Werten zwischen 9 und 11) und Haushaltsbleichen (Natriumhypochlorit) verhältnismäßig harmlos sind. Reiniger für maschinelles Geschirrspülen (Metasilikate), Abflußreiniger (Natronlauge) und Entkalker (Ameisensäure) sind stark ätzend und verursachen die Mehrzahl der schweren Verätzungsunfälle bei Kindern.

     

Vasodilation by medroxalol mediated by beta 2-adrenergic receptor stimulation

A contribution by active vasodilation to the hypotensive effect of medroxalol was investigated in anesthetized dogs and reserpinized pithed rats. In anesthetized dogs, intravenous doses of medroxalol, which decreased blood pressure and heart rate, also produced a dose-related vasodilation in the isolated perfused gracilis muscle in situ. This vasodilator effect of medroxalol was completely blocked by propranolol; the hypotensive effect of medroxalol was inhibited 50% by propranolol but not at all by practolol. In reserpinized pithed rats with angiotensin-supported blood pressure, intravenous doses of medroxalol also produced propranolol-sensitive decreases in diastolic blood pressure and did not alter heart rate. Labetalol produced similar effects but was significantly less potent. Comparatively, equivalent amounts of isoproterenol and pindolol decreased diastolic blood pressure but increased heart rate. In the isolated guinea pig trachea, medroxalol produced a propranolol-sensitive relaxation at concentrations that antagonized the relaxant effects of salbutamol. Identical concentrations of medroxalol did not increase rate of isolated guinea pig atria. It is concluded that a substantial portion of the hypotensive effect of medroxalol is due to a beta 2-adrenergic-receptor-mediated vasodilation.     

Inhibition of dopamine release by methylenedioxymethamphetamine is mediated by serotonin

(+/-)-3,4-Methylenedioxymethamphetamine (MDMA), at doses of 0.1, 1 and 10 mg/kg, produced a long-lasting decrease in extracellular dopamine concentration in the neostriatum of anesthetized rats, as measured by in vivo voltammetry. Since MDMA has been shown to release serotonin from rat brain slices and synaptosomes, we examined the possibility that increased serotonin release might be the cause of the decrease in dopamine release. Rats were treated with d,l-p-chloroamphetamine seven days prior to acute MDMA administration. Rats pretreated with p-chloroamphetamine, which produced a marked decrease in serotonin content, showed no significant decrease in extracellular dopamine concentration when administered 10 mg/kg MDMA. These data suggest that MDMA produces a significant decrease in dopamine release when administered acutely, and that this decrease is an indirect effect mediated by an increase in serotonin release.