The effect ofN-substituted alkyl groups on anticonvulsant activities ofN-Cbz-α-amino-N-alkylglutarimides

In order to examine the effects of N-substituted alkyl group on the anticonvulsant activities of N-Cbz-alpha-aminoglutarimides as novel anticonvulsants with broad spectrum, a series of (R) or (S) N-Cbz-alpha-amino-N-alkylglutarimides (1 and 2) were prepared from the corresponding (R) or (S) N-Cbz-glutamic acid and evaluated for the anticonvulsant activities in the maximal electroshock seizure (MES) test and pentylenetetrazol induced seizure (PTZ) test, including the neurotoxicity. The most potent compound in the MES test was (S) N-Cbz-alpha-amino-N-methylglutarimide (ED50=36.3 mg/kg, PI=1.7). This compound was also most potent in the PTZ test (ED50=12.5 mg/kg, PI=5.0). The order of anticonvulsant activities against the MES test as evaluated from ED50 values for (R) series was N-methyl > N-H > N-ethyl > N-allyl; for the (S) series N-methyl > N-H > N-ethyl > N-allyl > N-isobutyl compound. Against the PTZ tests, the order of anticonvulsant activities showed similar pattern; for the (R) series, N-methyl > N-H > N-ethyl > N-allyl; for the (S) series N-methyl > N-H > N-ethyl > N-allyl > N-isobutyl compound. From the above results, N-substituted alkyl groups were thought to play an important role for the anticonvulsant activities of N-Cbz-alpha-amino-N-alkylglutarimides.     

Synthesis and anticonvulsant activities ofN-Cbz-α-aminoglutarimidooxy carboxylate derivatives

Previous studies on the anticonvulsant activity of N-Cbz-alpha-aminoglutarimides have shown that the derivatives of N-Cbz-alpha-amino-N-alkoxy glutarimide have significant anticonvulsant activity. In addition, their anticonvulsant activities are dependent on the presence of N-alkoxy groups. Based on these results, a series of N-Cbz-alpha-amino-glutarimidooxy carboxylates derivatives (3a-e) were synthesized in moderate yield using a known synthetic procedure. Their anticonvulsant activities were evaluated using the maximal electroshock seizure (MES) test, the pentylene tetrazole induced seizure (PTZ) test, and the strychinine (Str) threshold test with the ultimate aim of developing more active anticonvulsants. None of the compounds (3a-e) tested showed anticonvulsant activity in the MES and PTZ test. However, all the compounds tested exhibited significant anticonvulsant activity in the Str. test. The most active compound in the Str. test was the methyl ester of N-Cbz-alpha-amino-glutarimidooxy acetic acid 3a (ED50 = 42.9 mg/kg).     

Legal high groups on the internet – The creation of new organized deviant groups?

Aims: To contribute to knowledge about the use of legal highs; the role of the internet in the purchase of legal highs; and to examine whether legal high groups on Facebook are acting as new organized deviant groups (ODGs) by facilitating and supporting the purchase and use of these substances and illegal alternatives.

Methods: Facebook was used to recruit respondents through a ‘legal high survey’ forum. Members of the group were directed to an online survey about their use and purchase of legal highs. The group's chat was monitored over a three-month period to observe their conversations about their use of legal (and illegal) drugs.

Findings: Respondents used legal highs for pleasure, out of curiosity or as an alternative to illegal drugs. Respondents were using illegal drugs and alcohol alongside legal highs. 48% of respondents agreed that they felt fully informed of the recommended dosage when purchasing legal highs online. There was evidence that online groups are acting as ODGs by protecting and neutralizing drug use and by informing and supporting novice users.

Conclusions: Policy makers should be concerned about the degree to which such groups encourage and reinforce the use of new substances, the safety of which is virtually unknown.     

"Groupdrink"? The effect of alcohol on risk attraction among groups versus individuals

OBJECTIVE: The objective of the present study is to assess the impact of alcohol consumption on the risk orientation of people when they are in groups as opposed to alone. Alcohol is often consumed within social groups, but previous research has not distinguished whether particular group processes affect risk differently as a consequence of alcohol consumption. Three theory-based predictions are tested to see whether, after alcohol consumption, groups encourage or inhibit risk as a result of group polarization, deindividuation, or group monitoring. METHOD: Male participants (N=120; ages 18-28), recruited via opportunity sample from students at the University of Kent, were assigned as individuals or as members of four-person groups. They had their breath alcohol concentration analyzed to ensure they were alcohol free and then were asked to consume either a placebo or alcohol in amounts equivalent to the legal limit for driving in the United States and the United Kingdom (.08% blood alcohol concentration). Participants completed a risk-attraction task either alone or in a group. Each participant also completed an alcohol-expectancy questionnaire. RESULTS: Individuals found risky choices significantly more attractive after consuming alcohol. In contrast, members of groups showed no such increase. In alcohol but not placebo conditions, groups made their decisions more slowly than did individuals. CONCLUSIONS: The results are consistent with the group-monitoring hypothesis (i.e., that group members attend to each other and promote a greater level of systematic processing of the risks presented). Results indicate that with moderate social drinking, groups may provide an informal means of mutual regulation and monitoring that can offset some aspects of alcohol myopia.     

The effect of chlorpromazine on the electrical activity of the “cerveau isolé”

Zusammenfassung Chlorpromazin (Largactil; Megaphen) verursachte in Dosen von 0,2–0,5 mg/kg (intravenös) ausgeprägte Veränderungen des Elektrocorticogramms des thalamo-corticalen Systems (cerveau isolé — Präparation von Bremer). Die für diese Präparation charakteristischen Spindeln (12–15 per sec) und langsamen Wellen (2–3 per sec) verschwanden innerhalb weniger Minuten nach der Injektion; in einigen Experimenten wurden vorübergehend spikes and waves im Anschluß an die intravenöse Injektion von Chlorpromazin beobachtet.Die Beobachtungen werden dahingehend interpretiert, daß Chlorpromazin die Spontanaktivität des thalamocorticalen Systems beeinflußt; diese Wirkung zusammen mit der früher beschriebenen blockierenden Wirkung auf die formatio reticularis des Hirnstammes vermag zu erklären, auf welche Weise Chlorpromazin den Zustand des Wachseins beeinflußt und dabei Veränderungen des Verhaltens verursacht.

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With 2 figures in the text.     

The effect of mandatory generic substitution on the safety of alendronate and patients’ adherence

Abstract

Objective:

Generic medicines are often used in public hospitals. However, data on the quality of generic alendronate, its efficacy, side-effects and medication adherence in clinical practice is scarce. Therefore, this study aimed to compare the side-effects and medication adherence of generic (apo-alendronate) and proprietary alendronate (Fosamax).     

The effect of formulative parameters on the size and physical stability of SLN based on “green” components

Cocoa butter (CB) is a largely used excipient in pharmaceutical field. Aim of this work was to set formulative parameters for the preparation of SLN based on “green” lipid matrix for drug delivery as natural, both human and environmental safe systems. Double emulsion technique (w₁/o/w₂) was selected for SLN preparation. The effect on the dimensional properties of different surfactants (Tween 80 and PEG 40 monostearate) and co-surfactants (PEG400 monostearate, Emulium® Kappa2 and Plurol®Stearique) at different concentrations was evaluated. Stability tests were performed. SLN dispersions were exsiccated and the effect of the dried process on SLN size was evaluated. The influence of temperature on SLN dimensions was investigated at 37?°C. MTT test was performed on raw materials and formulations. The w₁/o/w₂ is suitable, rapid and economic technique for the preparation of CB SLN. Tween 80-Plurol Stearique combination gives the best results: particles size less than 400?nm and PI of about 0.4 are obtained when PS 2% is used. Both raw materials and formulations are safe. The importance to evaluate the effect of different surfactant and/or co-surfactant on the dimensional properties of SLN is evident by selecting substances with preferable safety profiles, and favorable environmental properties to develop stable “green” SLN.     

The effect of α7 nicotinic receptor activation on glutamatergic transmission in the hippocampus

Nicotinic acetylcholine receptors (nAChRs) are expressed widely in the CNS, and mediate both synaptic and perisynaptic activities of endogenous cholinergic inputs and pharmacological actions of exogenous compounds (e.g., nicotine and choline). Behavioral studies indicate that nicotine improves such cognitive functions as learning and memory, however the cellular mechanism of these actions remains elusive. With help from newly developed biosensors and optogenetic tools, recent studies provide new insights on signaling mechanisms involved in the activation of nAChRs. Here we will review α7 nAChR’s action in the tri-synaptic pathway in the hippocampus. The effects of α7 nAChR activation via either exogenous compounds or endogenous cholinergic innervation are detailed for spontaneous and evoked glutamatergic synaptic transmission and synaptic plasticity, as well as the underlying signaling mechanisms. In summary, α7 nAChRs trigger intracellular calcium rise and calcium-dependent signaling pathways to enhance glutamate release and induce glutamatergic synaptic plasticity.     

The effect of stereochemistry on the thermodynamic characteristics of the binding of fenoterol stereoisomers to the β2-adrenoceptor

The binding thermodynamics of the stereoisomers of fenoterol, (R,R′)-, (S,S′)-, (R,S′)-, and (S,R′)-fenoterol, to the β₂-adrenergic receptor (β₂-AR) have been determined. The experiments utilized membranes obtained from HEK cells stably transfected with cDNA encoding human β₂-AR. Competitive displacement studies using [³H]CGP-12177 as the marker ligand were conducted at 4, 15, 25, 30 and 37 °C, the binding affinities calculated and the standard enthalpic (ΔH°) and standard entropic (ΔS°) contribution to the standard free energy change (ΔG°) associated with the binding process determined through the construction of van’t Hoff plots. The results indicate that the binding of (S,S′)- and (S,R′)-fenoterol were predominately enthalpy-driven processes while the binding of (R,R′)- and (R,S′)-fenoterol were entropy-driven. All of the fenoterol stereoisomers are full agonists of the β₂-AR, and, therefore, the results of this study are inconsistent with the previously described “thermodynamic agonist-antagonist discrimination”, in which the binding of an agonist to the β-AR is entropy-driven and the binding of an antagonist is enthalpy-driven. In addition, the data demonstrate that the chirality of the carbon atom containing the β-hydroxyl group of the fenoterol molecule (the β-OH carbon) is a key factor in the determination of whether the binding process will be enthalpy-driven or entropy-driven. When the configuration at the β-OH carbon is S the binding process is enthalpy-driven while the R configuration produces an entropy-driven process.     

α-Adrenoceptor-mediated inhibitory effect of the sympathetic nervous system on the isoprenaline-induced increase in plasma renin concentration

Summary The importance of the sympatho-adrenal system for the isoprenaline-induced increase in plasma renin concentration was investigated in conscious rats. Ganglionic blockade by trimethidinium (10 mg kg^–1) increased the dose-dependent elevation of plasma renin concentration induced by isoprenaline (0.03–0.48 g kg^–1 min^–1). Also treatment of the rats with guanethidine (6 mg kg^–1) or reserpine (2.5 mg kg^–1, given 16 and 7 h prior to the experiments) further increased the effect of isoprenaline (0.5 g kg^–1 min^–1) on plasma renin concentration. Unilateral renal denervation combined with contralateral nephrectomy doubled the effect of the -sympathomimetic amine on renin release. The -adrenoceptor antagonist phenoxybenzamine (3 mg kg^–1) also enhanced the effect of isoprenaline on this parameter.It is concluded that apart from a stimulation of renin release via -adrenoceptors the sympathetic nervous system may inhibit renin release via stimulation of -adrenoceptors.Supported by DFG Me 541/1Partial preliminary communication: Meyer et al. (1976)     

The effect of Polygonum multifiorum on the memory of AD rats and the APP cleaveing enzyme in their hippocampus

Objective. To approach the therapy mechanism of Polygonum multiflorum on AD. Methods. 30 AD rats were randomly divided into Polygonum multiflorum group （PMG） and physiological saline group （PSG） with 15 rats for each group. 15 young rats were selected as yong group （YG） .All rats were tested with maze, and were breeded at the experimental animal centre of Central South University. Lavaged with Polygonum multiflorum or physilological saline one time every day for total 4 weeks, The YG and PSG were lavaged with 1.5ml physiological saline injection every time,     

The effect of δ 9-tetrahydrocannabinol and LSD on the acquisition of an active avoidance response in the rat

The course of active avoidance learning of rats in a symmetrical Y-maze under the influence of 1, 3, and 9 mg/kg of ⁹-THC i.p., and 5, 20, and 100 g/kg of LSD was investigated. ⁹-THC in a dosage of 1 mg/kg had no effect on avoidance learning. Three and to a lesser extent 9 mg/kg produced more rapid learning with a significantly better performance. Learning under ⁹-THC proved to be statedependent. The withdrawal of ⁹-THC caused a decrease in the avoidance rate, which was dependent on the dosage. Upon renewal of the THC doses, the animals reattained their earlier performance. In the course of the experiment there was rapid tolerance development, especially of the sedative properties of THC.LSD retarded the rate of acquisition of the active avoidance response. Whereas the control animals displayed over 80% successful active avoidance from the 14th session onwards, this was achieved by the LSD groups only after the 20th session. However, in contrast to the control group the LSD animals were able to increase their avoidance rate to over 90%, and this was maintained to the end of the experiment (a total of 24 sessions with LSD). The sudden withdrawal of LSD produced a fall in avoidance rate, which was dependent on the previous training dosage; as with ⁹-THC state-dependent learning can also be assumed for LSD.     

The effect of pimozide on variable-interval performance: A test of the ‘anhedonia’ hypothesis of the mode of action of neuroleptics

A quantitative behavioural test system based on Herrnstein's (1970) equation was used to test a prediction derived from the anhedonia hypothesis of neuroleptic action, that pimozide should increase the value of the behavioural parameter K _H (the reinforcement frequency needed to maintain the half-maximal response rate in variable-interval schedules). On the basis of theoretical considerations, it was shown that the equation implies that a drug which exerts such an effect on K _H must have a more profound suppressant effect on performance maintained by low reinforcement frequencies than on performance maintained by high reinforcement frequencies. Fifteen rats were trained under variable-interval 10-s and variable-interval 100-s schedules, and the effect of pimozide (0.125, 0.25, 0.33, and 0.5 mg/kg) was tested on performance maintained under each schedule. The drug suppressed performance maintained under both schedules in a dose-dependent manner, and there was no tendency for the drug to exert a greater effect on performance maintained under the lower reinforcement frequency. These results do not provide any evidence that the effect of pimozide on variable-interval performance is due to an anti-hedonic effect; rather, they are compatible with the hypothesis that pimozide impairs the capacity to respond.     

The effect of pathophysiology on pharmacokinetics in the critically ill patient — Concepts appraised by the example of antimicrobial agents

Critically ill patients are at high risk for development of life-threatening infection leading to sepsis and multiple organ failure. Adequate antimicrobial therapy is pivotal for optimizing the chances of survival. However, efficient dosing is problematic because pathophysiological changes associated with critical illness impact on pharmacokinetics of mainly hydrophilic antimicrobials. Concentrations of hydrophilic antimicrobials may be increased because of decreased renal clearance due to acute kidney injury. Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by systemic inflammatory response syndrome, capillary leak, decreased protein binding and administration of intravenous fluids and inotropes. Often multiple conditions that may influence pharmacokinetics are present at the same time thereby excessively complicating the prediction of adequate concentrations. In general, conditions leading to underdosing are predominant. Yet, since prediction of serum concentrations remains difficult, therapeutic drug monitoring for individual fine-tuning of antimicrobial therapy seems the way forward.     

The effect of seasonal variation and secretion of sunitinib in sweat on the development of hand–foot syndrome

Background

Hand–foot syndrome (HFS) is a side effect of sunitinib with considerable impact on quality of life. Seasonal variation and hyperhydrosis are possibly correlated to occurrence of HFS. Therefore, we proposed to study the prevalence of HFS in different seasons retrospectively and to study the relationship between sunitinib sweat secretion and HFS prospectively.

Patients and methods

A retrospective cohort of 19 patients treated with sunitinib was used to determine seasonal prevalence of HFS. In a prospective study, sunitinib and N-desethyl sunitinib levels in sweat patches of 25 patients treated with sunitinib were quantified and correlated to severity of HFS.

Results

In the retrospective cohort, the patients suffered from more severe HFS during summertime compared with the rest of the year. In the prospective study, the cumulative amounts of sunitinib plus metabolite measured in the patches of the on-treatment phase (median 129.4 ng/patch) were higher than the off-treatment phase (median 39.5 ng/patch). A tendency was observed towards increasing amounts of drug per patch with increasing severity of HFS.

Conclusion

Patients experienced more HFS in summer time compared to other seasons. However, no statistically significant correlation between sunitinib sweat secretion and severity of HFS could be demonstrated within our patient cohort.     

The effect of (±)-dobutamine on adrenergic nerve endings

Summary Possible effects of (±)-dobutamine on adrenergic nerve endings were determined in experiments with ghosts of bovine chromaffin granules, with rat phaeochromocytoma (PC-12) cells and with the rat vas deferens. Dobutamine inhibited the vesicular uptake of a mixture of 70% adrenaline + 30% ³H-noradrenaline into ghosts, with an IC₅₀ of 1.7 mol/l. Dobutamine inhibited uptake, of ³H-noradrenaline in PC-12 cells (with an IC₅₀ of 0.38 mol/l) without being a substrate. However, dobutamine easily entered PC-12 cells by diffusion. After inhibition of MAO, COMT and vesicular uptake dobutamine (15 and 45 mol/l) released tritium from rat vasa deferentia preloaded with ³H-noradrenaline. Equi-inhibitory concentrations of dobutamine and desipramine (against uptake₁) were equireleasing. On the other hand, when MAO and vesicular uptake were intact, dobutamine (15 mol/l) increased the efflux of tritium from preloaded vasa deferentia much more than did an equi-inhibitory concentration of desipramine. Most of the released tritium was then ³H-DOPEG.Dobutamine is a potent inhibitor of uptake₁ as well as of vesicular uptake; moreover, it easily diffuses into adrenergic nerve endings. Hence, it blocks the neuronal and the vesicular re-uptake of noradrenaline; consequently, when MAO and vesicular uptake are intact, dobutamine increases the net leakage of noradrenaline from the storage vesicles, thereby leading to an efflux of deaminated metabolites. However, dobutamine is virtually unable to release noradrenaline into the extracellular space.Abbreviations COMT catechol-O-methyl transferase - DOPEG dihydroxyphenylglycol - DOMA dihydroxymandelic acid - MAO monoamine oxidase Supported by the Deutsche Forschungsgemeinschaft (Gr 490/5 and SFB 176) Send offprint requests to P. Fischer at the above address     

The effect of isoprenaline on plasma concentrations of immunoreactive β-endorphin and β-lipotropin in the conscious rat

Summary The effect of the -adrenoceptor agonist isoprenaline on the plasma concentrations of -endorphin (-E) and -lipotropin (-LPH) was investigated in conscious rats. Isoprenaline (i.m.) elevated plasma -endorphin-like immunoreactivity (-EI) as measured by radioimmunoassay of unextracted plasma, with peak values 24 min after drug administration. This effect was dose-dependent. The lowest effective dose of isoprenaline was 15 g kg^–1; 240 g kg^–1 exerted a maximum effect, raising plasma -EI about ten-fold above control values. Plasma vasopressin concentrations also increased in response to isoprenaline following a timecourse identical to that of plasma -EI. (±)-Propranolol (1 mg kg^–1) but not phentolamine (10 mg kg^–1) rendered isoprenaline (240 g kg^–1) injections almost ineffective. Because of the cross-reactivity of -LPH in the radioimmunoassay used, plasma was extracted by means of a cation exchange resin and subjected to gel chromatography on a Sephadex G-50 column, avoiding artefactual degradation of the peptides. In isoprenaline-treated rats about 50% of the -EI behaved similar to human -LPH, whereas 45% co-migrated with human -E; immunoreactivity corresponding to -LPH or -E comprised about 70% or 30%, respectively, in the plasma extract of vehicle-treated rats. Dexamethasone pretreatment reduced the isoprenaline-induced increase in plasma -EI by 87%, but left the simultaneous elevation of plasma vasopressin concentrations unchanged.These data demonstrate that isoprenaline stimulates -LPH and -E release in vivo. The possibility of an interrelationship between vasopressin and -E release is discussed.