Do arterial effects of antihypertensive drugs depend on subject's serum cholesterol?

Effects of antihypertensive treatment on large arteries may be influenced by the type of drug and concomitant risk factors such as blood cholesterol. To explore these possibilities we investigated the common carotid artery of 20 subjects with low cholesterol and 19 subjects with high cholesterol, all with essential hypertension, randomly allocated to 3 months of treatment with nitrendipine (20 mg/d) or trandolapril (2 mg/d). Carotid parameters were determined by recording instantaneous pressure (applanation tonometry) and diameter (echotracking device) and by modeling the pressure-diameter loop to obtain the Peterson modulus, stiffness index, measured and isobaric compliances, and wall viscosity. Effects of drugs on carotid parameters did not differ, except on systolic and diastolic diameters (p < 0.01), which increased insignificantly under nitrendipine but decreased (p < 0.01) under trandolapril. Blood cholesterol status did not influence carotid effects of trandolapril, whereas patients with low and high cholesterol treated with nitrendipine exhibited significant differences in drug effects on (a) systolic and pulse pressures (p < 0.05), which decreased in patients with low cholesterol (p < 0.01, p < 0.05) but not in those with high cholesterol; (b) diastolic diameter (p = 0.05), which increased insignificantly in patients with low cholesterol but was unchanged in those with high cholesterol; and (c) wall viscosity (p < 0.01), which decreased in patients with low cholesterol (p < 0.05) but increased insignificantly in those with high cholesterol. Also, wall viscosity change under nitrendipine was positively related to the baseline blood cholesterol ( r = 0.64, p < 0.01). Thus, nitrendipine and trandolapril show noteworthy differences in their effects on the carotid artery, in particular with respect to the status of blood cholesterol, but these differences should be confirmed by larger studies.     

What can isolated skeletal muscle experiments tell us about the effects of caffeine on exercise performance?

Caffeine is an increasingly popular nutritional supplement due to the legal, significant improvements in sporting performance that it has been documented to elicit, with minimal side effects. Therefore, the effects of caffeine on human performance continue to be a popular area of research as we strive to improve our understanding of this drug and make more precise recommendations for its use in sport. Although variations in exercise intensity seems to affect its ergogenic benefits, it is largely thought that caffeine can induce significant improvements in endurance, power and strength-based activities. There are a number of limitations to testing caffeine-induced effects on human performance that can be better controlled when investigating its effects on isolated muscles under in vitro conditions. The hydrophobic nature of caffeine results in a post-digestion distribution to all tissues of the body making it difficult to accurately quantify its key mechanism of action. This review considers the contribution of evidence from isolated muscle studies to our understating of the direct effects of caffeine on muscle during human performance. The body of in vitro evidence presented suggests that caffeine can directly potentiate skeletal muscle force, work and power, which may be important contributors to the performance-enhancing effects seen in humans.     

Does the effect of herbicide pulse exposure on aquatic plants depend on Kow or mode of action?

The highest concentrations of herbicides measured in flowing surface waters are often only present for short periods of time. These herbicide pulses can reach concentrations that would affect aquatic plants if present over a long time. The aim of this study was to assess the effect of a 3-h herbicide pulse relative to the effects of long-term (4 and 7 days) exposure of six herbicides with different sites of action and different K(ow) on the growth of the floating macrophyte Lemna minor. The herbicides were the two photosynthetic inhibitors: diquat and terbuthylazine, the inhibitors of acetolactate syntase (ALS), imazamox and metsulfuron-methyl and the microtubule assembly inhibitors propyzamide and pendimethalin. The log K(ow) ranged from -4.6 to 5.2. For imazamox, metsulfuron-methyl, propyzamide and pendimethalin a 3-h pulse induced the effect on area-specific growth as did a 4-day exposure at an approximate 10-fold higher concentration. For diquat and terbuthylazine a concentration closer to a factor of 100 or more was needed for a 3-h pulse to induce an effect similar to that of a 4-day exposure. For diquat, the low pulse-effect was most likely due to a slow uptake of the hydrophilic ion (log K(ow) = -4.6), as no effect was observed on chlorophyll fluorescence within 8 h after exposure. The chlorophyll fluorescence parameters are expected to respond quickly to a PSI inhibitor as diquat. For terbuthylazine, fluorescence measurements showed an effect on photosynthesis within 1h of exposure, and reached a minimum after 3 h. Recovery was fast, and initial fluorescence was restored within 24 h. Hence, the small pulse effect on area-specific growth was due to rapid recovery of photosynthesis. In contrast to terbuthylazine, the stop in area-specific growth observed for the ALS-and microtubule assembly inhibitors, took up to 4 days to recover from. Such a long recovery time after a pulse of only 3 h indicate that at realistic pulse exposures of up to a day or two, pulse-effects will approach the effects obtained in long-term studies. When investigating the effects of pulse exposures on aquatic plants, we should therefore focus more on non-photosynthetic inhibitors, which might not appear in pulses in as large concentrations as the PSII inhibitors investigated up till now, but whose effect, even in a shorter pulse, can be more damaging.     

Impact of estrogen therapy on Alzheimer's disease: a fork in the road?

The results of recent clinical studies have challenged our previously held view that estrogen therapy promotes neurological health and prevents or ameliorates Alzheimer's disease. A major question emerging from these studies is: how can there be such disparity between the basic science and epidemiological data that show that estrogen can protect neurons against degenerative insults and reduce the risk of Alzheimer's disease and the recent data (from the Women's Health Initiative Memory Study [WHIMS] trial and the trial of estrogen treatment for Alzheimer's disease), which show that hormone replacement therapy (HRT) showed no benefit and even a potential deleterious effect? Which set of data is correct? The proposition put forth in this review is that both sets of data are correct and that two major factors determine the efficacy of estrogen or HRT. First is the time at which estrogen therapy is initiated. The data indicate that initiation of therapy early in menopause and when neurons are in a healthy state, reduces the risk of Alzheimer's disease; whereas, estrogen therapy initiated after the disease has developed or decades following menopause is without benefit. Second, estrogen therapy is not the same as HRT and the type of progestogen used determines the outcome of the therapeutic intervention. Insights into the mechanisms of action of estrogen and progestogen in the brain provide a framework for understanding the paradox of the benefit of estrogen in the prevention of Alzheimer's disease versus the lack of benefit in treatment trials and in trials when HRT is instituted many years after menopause. Based on estrogen-inducible mechanisms, which have been elucidated in healthy neuron model systems, it would be predicted that estrogen therapy could be highly effective in preventing neurodegenerative disease by promoting neuronal defence and memory mechanisms. The mechanisms of action of estrogen also predict that estrogen therapy would be an ineffective strategy for reversing the pathology of Alzheimer's disease. In summary, the time at which estrogen therapy is initiated, the neurological status of the brain at the time of estrogen therapy initiation and the type of progestogen used all contribute to the efficacy of estrogen in preventing neurodegenerative disease and to sustaining neurological health and function. An estrogen advantage hypothesis is put forth that provides a unifying mechanism of estrogen action with implications for both the benefits and risks of estrogen therapy.     

Do animal models of anxiety predict anxiolytic-like effects of antidepressants?

Chronically administered antidepressant drugs, particularly selective serotonin (5-HT) reuptake inhibitors (SSRIs), are clinically effective in the treatment of all anxiety disorders, while the clinical effectiveness of "traditional" anxiolytics, such as benzodiazepines (BDZs), is limited to generalised anxiety disorder or acute panic attacks. This implies that animal models of anxiety should be sensitive to SSRIs and other antidepressants in order to have predictive validity. We reviewed the literature on the effects of antidepressants in the so-called animal models of anxiety and found that only the isolation-induced calls in guinea-pig pups may reveal anxiolytic-like action of all antidepressant classes after acute administration. Some other models, such as marble-burying or conditioned-freezing behaviours, and isolation- or shock-induced ultrasonic vocalisation models, may detect anxiolytic-like activity of acutely administered antidepressants, although the sensitivity of these models is usually limited to SSRIs and other drugs affecting 5-HT uptake. The predictive validity of models of "anxiety", such as the plus-maze and light-dark transition tests or stress-induced hyperthermia, appears to be limited to BDZ-related drugs. Far less work has been done on chronic administration of antidepressants in animal anxiety models. Unless and until such studies have been undertaken, the true predictive value of the anxiety models will remain unknown.     

Involvement of δ-opioid receptors in the effects of morphine on locomotor activity and the mesolimbic dopaminergic system in mice

Naltrindole (NTI) and naltriben (NTB), a benzofuran derivative of NTI, were recently synthesized as highly selective -opioid receptor antagonists. Both NTI and NTB failed to suppress the antinociceptive effect induced by morphine. In contrast, both NTI and NTB significantly suppressed the morphine-induced hyperlocomotion and increase in turnover of dopamine (DA) in the mouse limbic forebrain. These results suggest that -opioid receptors play, at least in part, a role in the morphine-induced hyperlocomotion and excitation of mesolimbic DA systems, but not antinociception.     

Do our guardians need guarding? An examination of the Australian system of self-regulation of alcohol advertising

In this study the Australian system of self-regulation of alcoholic beverage advertising was examined. Sixteen advertisements, eight print and eight television advertisements, were subjected to public scrutiny. Respondents rated advertisements using a self-completion questionnaire based directly on the Australian Alcoholic Beverage Advertising Code. Responses were collated and where a majority of respondents had endorsed items that constituted a breach of the cose, a complaint, ostensibly from a member of the general public, was made to the Advertising Standards Council. All sixteen advertisements were regarded by the public as containing aspects which breached the code. However, the Advertising Standards Council rejected all but one of the sixteen complaints, often directly contradicting the opinions of our respondents. The social policy implications of these results are considered. It is contended that the system of self-regulation of alcohol advertising does not serve the public interest.     

The role of the dynorphin–κ opioid system in the reinforcing effects of drugs of abuse

Background  

Initial hypotheses regarding the role of the κ opioid system in drug addiction suggested that κ receptor stimulation had anti-addictive effects. However, recent research suggests that κ receptor antagonists may reverse motivational aspects of dependence. In the present review, we revisit the studies that measured the effects of κ receptor ligands on the reinforcing and rewarding effects of drugs and postulate underlying neurobiological mechanisms for these effects to elaborate a more complex view of the role of κ receptor ligands in drug addiction.     

Testing the effects of hypnotics on memory via the telephone: fact or fiction?

The two benzodiazapines used in this experiment, namely midazolam and flunitrazepam, have both been shown to have effects on memory processing in laboratory studies. In spite of the potential hazards involved in real life testing, it should be possible to replicate such findings in everyday environments and it is argued that a successful replication would be a very meaningful extension to the existing laboratory data. The present study was successful in producing significant hangover effects in healthy volunteers using a novel user-friendly telephone testing technique. Compared to placebo, the two hypnotics reduced speed of processing in tasks which required retrieval from long-term semantic memory (semantic verification) and the manipulation of material in working memory (syntactic reasoning). We suggest that this new method offers the potential for carrying out large-scale psychopharmacological studies with real patients and achieves a meaningful step forward in the search for ecological validity.     

Study on effects of cinobufagin on the immunologic function of mice in vitro

华蟾毒精对小鼠免疫功能影响的体外研究@宋宇$College of Animal Science and Veterinary Medicine,Jilin University!Changchun 130062,Jilin,China;National Standard Laboratory of Pharmacology for Traditional Chinese Medicine, Jilin Natural Pharmatech Co.Ltd, Chang     

Do zopiclone, zolpidem and flunitrazepam have residual effects on simulated task of collision anticipation?

Few studies have addressed the modifications in visual information processing brought about by taking hypnotic substances. The present experiment with healthy subjects investigated the residual effects of taking a single night-time dose of hypnotics on collision anticipation capacities the next morning. Visual sequences simulated the movement of a driver approaching an intersection where another vehicle was arriving. Ten participants had to estimate, as quickly as possible, whether the other vehicle would arrive before or after them at the intersection. They were tested after having taken a capsule of zolpidem (10 mg), zopiclone (7.5 mg), flunitrazepam (1 mg) or a placebo. The results show no residual effects of the molecules. Only flunitrazepam, a benzodiazepine with a long half-life, appears to cause subjects to focus their attention on an element which, while relevant for the task (a road sign playing the role of a spatial reference), is not used correctly.     

Inhibitory effects on the discriminative stimulus properties ofd-amphetamine by classical and newer antipsychotics do not correlate with antipsychotic activity. Relation to effects on the reward system?

Classical antipsychotics exemplified by haloperidol (0.30), fluphenazine (0.070) andcis(Z)-flupentixol (0.088; ED₅₀ values in µmol/kg are given in parentheses for all compounds) potently block the discriminative stimulus properties ofd-amphetamine (1.0 mg/kg, IP) in rats. Newer antipsychotics have very different profiles: clozapine (7.2) and olanzapine (5.9) induce dose-dependent inhibition, while risperidone (>6.1) and remoxipride (>47) show weak inhibitory effects and sertindole (>23), seroquel (>20), amperozide (>2.9) and the putative antipsychotic MDL 100151 (>13; racemate with MDL 100907 as the active enantiomer) are ineffective. Antagonists of ₁-adrenoceptors (prazosin; >6.0), 5-HT_2A/2C (ritanserin; >2.6) and histamine H₁ receptors (mepyramine; >50) are ineffective. Sertindole (0.076), risperidone (0.23), clozapine (0.39), olanzapine (0.088), MDL 100151 (0.0082), fluphenazine (0.13) and ritanserin (0.12) are potent inhibitors of the discriminative stimulus induced by the 5-HT_2A/2C agonist DOI (0.63 mg/kg, IP), while haloperidol (0.4),cis(Z)-flupentixol(0.04), amperozide (0.5) and prazosin (>12) show partial inhibition and remoxipride (>23) and mepyramine (>25) are ineffective. The results indicate that inhibition ofd-amphetamine discrimination does not correlate with antipsychotic activity of newer antipsychotics, as has previously been suggested in the literature. Furthermore, the inhibitory potencies againstd-amphetamine-induced discrimination (present study) and hypermotility (previous study in the same strain of rats) do not correlate either for several of the newer antipsychotics (e.g. for sertindole, risperidone, seroquel and remoxipride). The discrepancies cannot solely be explained by additional pharmacological effects of these compounds, e.g. 5-HT₂ receptor blockade. Thed-amphetamine discrimination is documented to depend on increased limbic dopamine function which in humans is associated with increased euphoria. Based on these results, it is hypothesized thatd-amphetamine discrimination rather than a model for antipsychotic activity may reflect dysphoric or anhedonic activity.     

Do different mechanisms underlie two anxiogenic effects of systemic nicotine?

Alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) and 5-hydroxytryptamine 1A (5-HT1A) receptors have been implicated in the anxiogenic effects of centrally administered nicotine, but the receptors that mediate the anxiogenic effects of systemic nicotine are not known. This study explored whether competitive nAChR antagonists [dihydro-beta-erythroidine (DHbetaE), 4 mg/kg, and methyllycaconitine (MLA), 5 mg/kg], and a 5-HT1A receptor antagonist (WAY 100635, 0.5 and 1 mg/kg) could block the effects of two anxiogenic doses of nicotine in the social interaction test of anxiety. The anxiogenic effect of 0.1 mg/kg nicotine, given 5 min before the test, was blocked by DHbetaE and WAY 100635, establishing roles for alpha4beta2 nAChRs and 5-HT1A receptors. None of the antagonists could block the effect of 0.45 mg/kg nicotine, given 30 min before the test, precluding firm conclusions about the mechanisms underlying this anxiogenic effect. However, there was evidence for a role of alpha7 nAChRs in mediating an endogenous anxiogenic tone, since MLA itself had an anxiolytic effect that was blocked by both doses of nicotine. Thus, both alpha7 and alpha4beta2 nAChRs might have a role in mediating the anxiogenic effects of nicotine.     

Do adolescent smokers experience withdrawal effects when deprived of nicotine?

This is the first controlled prospective study of the effects of nicotine deprivation in adolescent smokers. Heart rate and subjective withdrawal symptoms were measured over an 8-hr period while participants smoked normally. Seven days later, participants were randomized to wear a 15-mg (16-hr) nicotine patch or a placebo patch for 8 hr, and they refrained from smoking during the session. Those wearing the placebo experienced a decrease in heart rate across sessions and an increase in subjective measures of nicotine withdrawal. Those wearing the active patch also reported significant increases for some subjective symptoms. Expectancy effects were also observed. The findings indicate that adolescent smokers experience subjective and objective changes when deprived of nicotine. As in previous research with adults, expectancies concerning the effects of nicotine replacement also influenced perceptions of withdrawal.     

Do effects of mercury in larval amphibians persist after metamorphosis?

Despite widespread concern about the role of environmental contaminants in global amphibian declines, and evidence that post-metamorphic life stages contribute disproportionately to amphibian population dynamics, most studies in amphibian ecotoxicology focus on larval life stages. Studies that focus solely on early life stages may miss important effects of contaminant exposure, such as latent effects that manifest some time after previous exposure. Moreover, it is often assumed that effects observed in amphibian larvae will persist to affect survival or reproduction later in life. We used terrestrial enclosures to determine whether exposure to mercury (Hg) through maternal transfer and/or larval diet had any adverse effects in post-metamorphic American toads (Bufo americanus). We found a 5% difference in size at metamorphosis that was attributed to maternal Hg exposure persisted for 1 year in the terrestrial environment, resulting in a 7% difference at the conclusion of the study. Although patterns of survival differed among treatments through time, we found no overall difference in survival after 1 year. We also found no evidence of emergent latent effects in the terrestrial toads that could be attributed to earlier exposure. Our results indicate that adverse effects of maternal Hg exposure that were observed in larval amphibians may persist to affect later terrestrial life stages but that no novel adverse effects developed when animals were raised in a semi-natural environment. Moreover, we found no evidence of persistent effects of dietary Hg exposure in larvae, highlighting a need for greater focus on maternal effects in amphibian ecotoxicology. Finally, we suggest an increase in the use of longitudinal studies to better understand contaminant impacts to amphibian populations via effects in both aquatic and terrestrial life stages.     

Why do estimates of the acute and chronic effects of air pollution on mortality differ?

Several investigators have discussed various reasons for the large and consistent difference in the relative risk estimates per unit exposure to air pollution derived from time-series and cohort study designs. This article considers whether the two study designs are estimating fundamentally different parameters even though both are commonly expressed in terms of relative risk coefficients. A frailty model for air pollution mortality is proposed to illustrate some of the theoretical behaviors of heterogeneous populations exposed to time-varying pollution patterns and their implications for the kinds of summary measures widely used in air pollution risk assessment.     

Do triglycerides modulate the effectiveness of clozapine?

We describe a case in which a patient's clinical response to clozapine appears to correlate positively with his serum triglyceride concentrations. We propose that the observed clinical response may partly be the result of the physical interaction of clozapine with the very low-density lipoproteins. We base this supposition on our previous in-vitro study showing that the plasma distribution of clozapine is significantly altered by increases in plasma triglyceride concentrations. Although this case only represents one patient, it highlights the possibility that serum lipids may be potential contributors to the clinical effectiveness of clozapine.     

Halogenation effects of pheniramines on the complexation with β-cyclodextrin

This study investigated the inclusion complexes of β-cyclodextrin with pheniramine and its halogenated derivatives chlorpheniramine and brompheniramine both experimentally and theoretically to characterize the effects of a halogenated phenyl ring on the intermolecular interactions. Fourier transform infrared and nuclear magnetic resonance (NMR) experiments provided evidence of the formation of inclusion complexes and NMR were conducted to evaluate the apparent binding constants. The two-layered hybrid ONIOM method, ONIOM(B3LYP/6-31G(d):PM3), was adopted to optimize the geometry. The linear relationships between the calculated and experimental values for frequencies (with a scaling factor of 0.96) and for magnetic properties (with a scaling factor of 1.05) demonstrate that the quantum chemical calculations were consistent with the experimental spectra. Additionally, the calculated binding energies were consistent with the experimental results: the stability order of the complexes and the trend of the binding energy is: brompheniramine > chlorpheniramine > pheniramine; S-enantiomer > R-enantiomer. Natural Bond Orbital analysis further demonstrated three major electronic delocalizations—from the substituent on the phenyl moiety of pheniramine to β-CD and from β-CD to the phenyl and amine moieties in pheniramine—which were the dominant intermolecular forces that were responsible for the substantially different binding strengths. Geometrical data and the partial charge distribution obtained by NBO analysis are provided as supplementary data.