USE OF TRANQUILIZERS IN DISEASES OF THE SKIN—A Preliminary Report

Tranquilizing agents such as chlorpromazine and reserpine were used in various diseases of the skin in which the psychogenic factors were considered important etiologic agents. While a tranquilizing effect was obtained in the majority of instances, the side reactions and variation in response were so great as to render these agents unsatisfactory for routine use as tranquilizers. Meprobamate (marketed under the trade names Miltown and Equanil) was then used on a group of dermatologic patients with more consistent tranquilizing effect and comparatively little unpleasant side reactions. It is felt that further study of the use of meprobamate as a tranquilizing agent in dermatology is worth while.     

Participation of GABA-ergic structures in producing the effects of haloperidol

A study was made of the effect of haloperidol on convulsions induced in mice by bicuculline and thiosemicarbazide and on the recovery cycles of the primary response in the rat sensorimotor cortex. In doses of 0.3--0.5 mg/kg producing a tranquilizing effect, haloperidol exerts a protective action in convulsions induced by bicuculline blocking of the GABA receptors and enhances the depression of the testing response during recovery cycle of the rat sensorimotor cortex primary response. It means that over this dosage range haloperidol potentiates GABA-induced effects. An increase in the neuroleptic dose up to 1--2 mg/kg entails disappearance of the efficacy shown by both the tests. The authors' own and reported data suggest an important role played by the postsynaptic GABA-positive effect in realization of the tranquilizing action of haloperidol and other neurotropic agents.     

Unexpected Ca2+-mobilization of oxaliplatin via H1 histamine receptors

Oxaliplatin is a widely used chemotherapeutic drug and represents the cornerstone of colorectal cancer therapy, in combination with 5-fluorouracil and folinic acid. As with many chemotherapeutic agents, its use is associated with a number of side effects, ranging from hypersensitivity reactions to haematological dyscrasias. Oxaliplatin also induces acute and chronic peripheral neuropathy.While it is likely that the haematological side effects are associated with its anti-proliferative effects and with the ability to form DNA adducts, the molecular mechanisms underlying peripheral neuropathy and hypersensitivity reactions are poorly understood, and therefore the choice of adequate supportive therapies is largely empirical.Here we show that an acute low dose oxaliplatin application on DRG neurons is able to induce an increase in intracellular calcium that is dependent on the Histamine 1 receptor (H1). Oxaliplatin-induced intracellular calcium rises are blocked by two selective H1 antagonist, as well as by U73122, a PLC inhibitor, and by 2-APB, a non-specific IP₃ receptor blocker. Moreover, expression of the H1 receptor on HEK293 t cells unmasks an oxaliplatin-induced Ca²⁺-rise. Last, activation of H1 via either histamine or oxaliplatin activates TRPV1 receptors, a mechanism that has been associated with itch. These data, together with literature data that has shown that anti-histamine agents reduce the incidence of oxaliplatin-induced hypersensitivity, may provide a molecular mechanism of this side effect in oncological patients.     

Tranquilizing effect of n-dipropylacetate and other GABA-ergic substances in conflict situations

Effect of n-dipropyl acetate (n-DPA), amino oxyacetic acid (AOAA), pantogam and piracetam on rat behaviour was studied under conflict situation. n-DPA, AOAA and piracetam increased significantly the main index of the tranquilizing action, that is the number of water intakes from the drinking bowl, supported by electric stimulation. This effect was most pronounced in n-DPA. Bicuculline and corasol almost completely eliminated the tranquilizing effect of n-DPA, while this effect was abolished by caffeine only by 50%.     

Halide concentrations in camel plasma in various states of hydration

Instrumental epithermal neutron activation analysis was used in determining the halide concentration of camel serum. The halides determined were sodium, chloride, bromide, and iodide. Serum was examined when the camels had free access to drinking water, following 10 d of water restriction and 2 h following rapid rehydration. When the camels were dehydrated there was a “serum storage” of iodide. This confirms the decline in thyroid metabolism previously described (15). Following rehydration the thyroid metabolism returned to normal. Dehydration also increased the serum bromide concentrations. This could have a tranquilizing effect, abetting the decrease in metabolism. There were no changes in sodium or chloride metabolism. It is concluded that use of neutron activation will allow an analysis of halides for physiological research.     

Development of passivity in the rat: effect of tranquilizers and antidepressants

Following the views on passivity as one of the features of depression-like behaviour in rats developing as a result of unavoidable painful stimulation an attempt was made to eliminate by antidepressant drugs the passivity manifested in an almost complete absence of motor searching reactions in an "open field" and a maze. However tranquilizing drugs rather than antidepressants to a greater extent induced the effect presupposed. Hence the type of passivity under study corresponds more likely to neurotized behaviour than to a special depression-like. In the second series of experiments the action was studied of multiple injections of antidepressants on similar manifestations of passivity as well as on alimentary instrumental conditioned responses in rats with initially expressed passive character of behaviour. In this case too neither the presupposed increase of motor searching reaction was observed nor any significant changes in the rate of instrumental conditioning nor elimination of its failures of a "refuse" type.     

Peroxidase and pseudoperoxidase reactions in relation to sudanophilia.

A selective staining of hemoglobin in erythroid cell series was achieved by use of Sudan Black B (modified method of Sheehan and Storey) if optimal amount of hydrogen peroxide was added to the staining mixture. The effect of some inhibitory agents (KCN, wet heat, pH) on this staining as well as on the Lepehne's pseudoperoxidase reaction for hemoglobin was similar. Both reactions were more resistant to these factors than the peroxidase reactions and sudanophilia in granulocytes in which both could be blocked by the pretreatment with absolute methanol. Moreover the effect of some extraction procedures for lipids on both myeloperoxidase reactions and sudanophilia was investigated. The results support the view that the sudanophilia in granulocytes is due to their peroxidase activity and for the staining of hemoglobin by use of Sudan Black B with H2O2 its pseudoperoxidase activity is responsible. In addition the effect of the substitution of phenolphosphate by dihydroxybenzenes on granulocyte sudanophilia is reported.     

The Use of Hydrogen Peroxide for Closing Disulfide Bridges in Peptides

The use of hydrogen peroxide for the formation of disulfide bridges was studied in 15 peptides of various lengths and structures. The oxidation of peptide thiols by hydrogen peroxide was shown to proceed under mild conditions without noticeable side reactions of Trp, Tyr, and Met residues. Yields of the corresponding cyclic disulfides were high and mostly exceeded those obtained with other oxidative agents, in particular, iodine. It was established that the use of hydrogen peroxide in organic medium also provided sufficiently high yields when large-scale syntheses of oxytocin and octreotide (up to 10 g) were carried out.     

Measurement of Side Effects of Drugs

In a clinical trial of two antirheumatic agents two methods of collection of side effects were used, one with and the other without a check list of possible symptoms. Findings suggested that the use of a check list interfered with the collection of side effects. Known side effects of aspirin—tinnitus, deafness, and gastrointestinal disturbance—were more efficiently shown and symptoms not included in the check list were more likely to be reported when a check list was not used.     

Effect of diazepam on the formation and reproduction of conditioned cortical reactions in man

Intramuscular injections of seduxen (10 mg), a benzodiasepin drug, with expressed tranquilizing and alarm suppressing effects, were used with the aim of experimental testing of a hypothesis on the neural mechanism of conditioned changes of the P300 wave. Under the action of seduxen no temporary connections could be formed between a perceived nonverbal visual stimulus and a unrecognized emotional word. The seduxen did not suppress the conditioned cortical reaction acquired due to combination of nonverbal stimulus with unrecognized emotional word. The suggestion is made that the necessary condition of temporary connection elaboration by means of a unrecognized verbal stimulus is the implication of the limbic structures where negative emotional reactions are integrated.     

Hydrophobic chitosan microparticles: heterogeneous phase reaction of chitosan with hydrophobic carbonyl reagents

Hydrophobically modified chitosan microparticles were produced by various syntheses carried out as heterogeneous phase reactions. Perfluorinated carbonyl components such as carbonic acids and acid chlorides were used as hydrophobization agents. To enhance the layer stability preceding cross-linkages between the chitosan macromolecules were introduced. These cross-linkages involve some of the chitosan amino groups. The use of a highly reactive alkylene-maleic anhydride copolymer produces cross-linkages and hydrophobizes the chitosan layer simultaneously in a one-step reaction. The heterogeneous reactions serve as model reactions for the hydrophobization of chitosan films deposited on supports.     

Peroxidase and pseudoperoxidase reactions in relation to sudanophilia

Summary A selective staining of hemoglobin in erythroid cell series was achieved by use of Sudan Black B (modified method of Sheehan and Storey) if optimal amount of hydrogen peroxide was added to the staining mixture. The effect of some inhibitory agents (KCN, wet heat, pH) on this staining as well as on the Lepehne's pseudoperoxidase reaction for hemoglobin was similar. Both reactions were more resistant to these factors than the peroxidase reactions and sudanophilia in granulocytes in which both could be blocked by the pretreatment with absolute methanol. Moreover the effect of some extraction procedures for lipids on both myeloperoxidase reactions and sudanophilia was investigated. The results support the view that the sudanophilia in granulocytes is due to their peroxidase activity and for the staining of hemoglobin by use of Sudan Black B with H₂O₂ its pseudoperoxidase activity is responsible. In addition the effect of the substitution of phenolphosphate by dihydroxybenzenes on granulocyte sudanophilia is reported.     

Do we need an intravenous fluoroquinolone?

Intravenous ciprofloxacin, the first parenteral fluoroquinolone available in this country, represents another class of antimicrobial agents from which physicians must choose when treating nosocomial infections. Fluoroquinolones are bactericidal antimicrobial agents that act by inhibiting DNA gyrase. They are active in vitro against most gram-negative bacteria and methicillin-susceptible staphylococci. Activity against anaerobic bacteria and streptococci is poor. The rapid development of bacterial resistance in centers with high quinolone usage is of great concern. Resistance develops most commonly in Pseudomonas aeruginosa and staphylococci. Resistance emerges most often when quinolones are used to treat chronic infections or in patients with poorly drained abscesses, necrotic tissue, or indwelling catheters. Clinical trials have shown ciprofloxacin to be as effective as ceftazidime in the treatment of infections caused by gram-negative bacteria. Although the overall frequency of side effects to fluoroquinolones is low, seizures and allergic reactions have been attributed to their use. Ciprofloxacin inhibits the metabolism of theophylline, and morbidity and death have been reported in patients taking the two drugs concomitantly. Parenteral fluoroquinolones should be reserved for the treatment of gram-negative bacterial infections in patients in whom standard agents cannot be used.     

A fluorometric assay of acyl-CoA oxidase activity by a coupled peroxidatic reaction: elimination of interfering side reactions.

We have developed a simple, reliable, and sensitive method for the assay of peroxisomal fatty acyl-CoA oxidase (FAO, EC 1.13.-) in subcellular fractions. It is based on a peroxidase-linked oxidation of 4-hydroxyphenylacetic acid to a fluorescent compound [M.S. Poosch and R.K. Yamasaki (1986) Biochim. Biophys. Acta 884, 585-593]. Our method eliminates the contribution of important interfering side reactions, notably those due to the presence of reducing agents, which function as competitive substrates to 4-hydroxyphenylacetic acid. Rapidly reacting thiol groups are of particular importance, notably CoASH present endogenously (e.g. in peroxisomes and mitochondria) or formed by enzymatic hydrolysis of acyl-CoA. Alkylation of the thiol compounds by N-ethylmaleimide eliminates this disturbing side reaction, and increases the amount of fluorescent product in the coupled peroxidatic reaction. The method is suitable for routine assay of FAO activity in a wide range of tissues, notably in those with a low specific peroxisomal beta-oxidation activity and/or a high content of reducing agents. As an example of this we have included data from rat heart peroxisomal fractions. The effect of alkylation of sulfhydryl groups in the incubation mixture also applies to other oxidase reactions based on H2O2-coupled peroxidatic reactions, if the oxidase itself does not contain functional sulfhydryl groups.     

植物生长调节剂的研究及应用进展

植物生长调节剂是合成植物激素,其可以调节植物的代谢和生理功能,并且已广泛用于农业、林业和其他领域。而植物生长调节剂本身存在的毒副作用所引起的安全问题也不容忽视,在使用调节剂时应保证其安全性和有效性。文章概述了植物生长调节剂的种类、作用功效、国内外植物生长剂的研究和应用情况及在使用中存在的问题,分析了调节剂药效的影响因素,就植物生长调节剂的进一步应用提出了建议,进行了展望,并对其应用于生态修复领域的可行性进行了分析。植物生长调节剂在使用时应注意:(1)适时适量;(2)多种药型谨慎搭配,科学调控植物生长剂的使用;(3)植物生长调节剂不能随意与农药搭配以避免不良反应的发生。     

Structural optimization and evaluation of butenolides as potent antifouling agents: modification of the side chain affects the biological activities of compounds

A recent global ban on the use of organotin compounds as antifouling agents has increased the need for safe and effective antifouling compounds. In this study, a series of new butenolide derivatives with various amine side chains was synthesized and evaluated for their anti-larval settlement activities in the barnacle, Balanus amphitrite. Side chain modification of butenolide resulted in butenolides 3c-3d, which possessed desirable physico-chemical properties and demonstrated highly effective non-toxic anti-larval settlement efficacy. A structure-activity relationship analysis revealed that varying the alkyl side chain had a notable effect on anti-larval settlement activity and that seven to eight carbon alkyl side chains with a tert-butyloxycarbonyl (Boc) substituent on an amine terminal were optimal in terms of bioactivity. Analysis of the physico-chemical profile of butenolide analogues indicated that lipophilicity is a very important physico-chemical parameter contributing to bioactivity.     

Correlation between the experimental and clinical effectiveness of benzodiazepines and their affinity for benzodiazepine receptors

The therapeutic effect of 6 benzodiazepine tranquilizers (diazepam, oxazepam, chlordiazepoxide, phenazepam, lorazepam, nitrazepam) was compared to the activity displayed in the most widely used experimental models. The methods of conflict situation, antagonism with thiosemicarbazide and corasole were found to be highly significant for predicting the clinical efficacy of benzodiazepines. The conditioned reflex techniques were shown untenable for estimating the therapeutic action of the tranquilizers. The correlation was discovered between integral clinical tranquilizing effects of benzodiazepines, their experimental activity and affinity to benzodiazepine receptors.     

Carminomycin study in breast cancer]

Karminomycin was used for the treatment of cases with disseminated cancer of the mammary gland in doses of 5 mg/m2 of the body surface intravenously every day for 5 days (15 patients) or 6 mg/m2 twice a week for 2-3 weeks (30 patients). Partial remission or diminution of the tumor size at least by 50 per cent was observed in 26 and 17 per cent of the patients respectively. The remission duration was from 2 to 6 months. With the use of the shortperiod scheme the frequency of the direct side reactions increased. Leucopenia as a side effect was registered in 100 and 40 per cent of the patients and thrombocytopenia was registered in 18 and 3 per cent of the cases respectively.     

Rauwolfia serpentina; prolonged use in elderly hypertensive patients

In a group of older, arteriosclerotic hypertensive patients treated with an extract of Rauwolfia over a long period, a mild hypotensive effect was noted after weeks, or occasionally months, of therapy. No dramatic responses were seen, but the so-called "tranquilizing" effect was readily apparent and was appreciated by the patients. Side effects were usually relatively minor, were transient and rarely necessitated stopping the drug.     

Use of hydrogen peroxide for closing disulfide bridges in peptides

The use of hydrogen peroxide for the formation of disulfide bridges was studied in 15 peptides of various lengths and structures. The oxidation of peptide thiols by hydrogen peroxide was shown to proceed under mild conditions without noticeable side reactions of Trp, Tyr, and Met residues. Yields of the corresponding cyclic disulfides were high and mostly exceeded those obtained with other oxidative agents, in particular, iodine. It was established that the use of hydrogen peroxide in organic medium also provided sufficiently high yields when large-scale syntheses of oxytocin and octreotide (up to 10 g) were carried out. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 2; see also http://www.maik.ru.