Main Effect Of Drug Research Articles

Effects of risperidone, amisulpride and nicotine on eye movement control and their modulation by schizotypy

The increasing demand to develop more efficient compounds to treat cognitive impairments in schizophrenia has led to the development of experimental model systems. One such model system combines the study of surrogate populations expressing high levels of schizotypy with oculomotor biomarkers. We aimed (1) to replicate oculomotor deficits in a psychometric schizotypy sample and (2) to investigate whether the expected deficits can be remedied by compounds shown to ameliorate impairments in schizophrenia. In this randomized double-blind, placebo-controlled study 233 healthy participants performed prosaccade (PS), antisaccade (AS) and smooth pursuit eye movement (SPEM) tasks after being randomly assigned to one of four drug groups (nicotine, risperidone, amisulpride, placebo). Participants were classified into medium- and high-schizotypy groups based on their scores on the Schizotypal Personality Questionnaire (SPQ, Raine (Schizophr Bull 17:555-564, 1991)). AS error rate showed a main effect of Drug (p < 0.01), with nicotine improving performance, and a Drug by Schizotypy interaction (p = 0.04), indicating higher error rates in medium schizotypes (p = 0.01) but not high schizotypes under risperidone compared to placebo. High schizotypes had higher error rates than medium schizotypes under placebo (p = 0.03). There was a main effect of Drug for saccadic peak velocity and SPEM velocity gain (both p ≤ 0.01) indicating impaired performance with risperidone. We replicate the observation of AS impairments in high schizotypy under placebo and show that nicotine enhances performance irrespective of group status. Caution should be exerted in applying this model as no beneficial effects of antipsychotics were seen in high schizotypes.

Clinical Neuroprotective Drugs for Treatment and Prevention of Stroke

Stroke is an enormous public health problem with an imperative need for more effective therapies. In therapies for ischemic stroke, tissue plasminogen activators, antiplatelet agents and anticoagulants are used mainly for their antithrombotic effects. However, free radical scavengers, minocycline and growth factors have shown neuroprotective effects in the treatment of stroke, while antihypertensive drugs, lipid-lowering drugs and hypoglycemic drugs have shown beneficial effects for the prevention of stroke. In the present review, we evaluate the treatment and prevention of stroke in light of clinical studies and discuss new anti-stroke effects other than the main effects of drugs, focusing on optimal pharmacotherapy.

Lack of noradrenergic modulation of indirect semantic priming.

Norepinephrine and dopamine are both believed to affect signal-to-noise in the cerebral cortex. Dopaminergic agents appear to modulate semantic networks during indirect semantic priming, but do not appear to affect problem solving dependent on access to semantic networks. Noradrenergic agents, though, do affect semantic network dependent problem solving. We wished to examine whether noradrenergic agents affect indirect semantic priming. Subjects attended three sessions: one each after propranolol (40 mg) (noradrenergic antagonist), ephedrine (25 mg) (noradrenergic agonist), and placebo. During each session, closely related, distantly related, and unrelated pairs were presented. Reaction times for a lexical decision task on the target words (second word in the pair) were recorded. No decrease in indirect semantic priming occurred with ephedrine. Furthermore, across all three drugs, a main effect of semantic relatedness was found, but no main effect of drug, and no drug/semantic relatedness interaction effect. These findings suggest that noradrenergic agents, with these drugs and at these doses, do not affect indirect semantic priming with the potency of dopaminergic drugs at the doses previously studied. In the context of this previous work, this suggests that more automatic processes such as priming and more controlled searches of the lexical and semantic networks such as problem solving may be mediated, at least in part, by distinct mechanisms with differing effects of pharmacological modulation.

Lack of Noradrenergic Modulation of Indirect Semantic Priming

Norepinephrine and dopamine are both believed to affect signal-to-noise in the cerebral cortex. Dopaminergic agents appear to modulate semantic networks during indirect semantic priming, but do not appear to affect problem solving dependent on access to semantic networks. Noradrenergic agents, though, do affect semantic network dependent problem solving. We wished to examine whether noradrenergic agents affect indirect semantic priming. Subjects attended three sessions: one each after propranolol (40 mg) (noradrenergic antagonist), ephedrine (25 mg) (noradrenergic agonist), and placebo. During each session, closely related, distantly related, and unrelated pairs were presented. Reaction times for a lexical decision task on the target words (second word in the pair) were recorded. No decrease in indirect semantic priming occurred with ephedrine. Furthermore, across all three drugs, a main effect of semantic relatedness was found, but no main effect of drug, and no drug/semantic relatedness interaction effect. These findings suggest that noradrenergic agents, with these drugs and at these doses, do not affect indirect semantic priming with the potency of dopaminergic drugs at the doses previously studied. In the context of this previous work, this suggests that more automatic processes such as priming and more controlled searches of the lexical and semantic networks such as problem solving may be mediated, at least in part, by distinct mechanisms with differing effects of pharmacological modulation.

Differential effects of acute cocaine and placebo administration on visual cortical activation in healthy subjects measured using BOLD fMRI

Many blood oxygenation level dependent (BOLD) functional magnetic resonance imaging studies have shown a strong response due to cocaine in brain regions with high concentrations of dopamine receptors. However, cocaine also has non-specific effects, including cardiovascular changes that may cause changes in BOLD signals, raising the possibility that measured changes could be due to these non-specific effects. The following experiment was conducted to address this concern. Subjects were given either cocaine or saline infusions during a long BOLD functional magnetic resonance imaging study. A flashing uniform-field stimulus, periodically alternating between on and off, provided a strong activation of primary visual cortex. There was a significant main effect of drug between cocaine and placebo. Although we did not demonstrate a significant drug × time interaction, BOLD signal changes associated with visual stimulation appeared unchanged after cocaine administration, whereas the signal differences appeared to decrease during placebo. Explanation of the differential response between the two groups may reflect cocaine expectancy instead of a direct effect of cocaine on BOLD signal changes but will require further investigation to fully elucidate.

Nicotine Effect on Prepulse Inhibition and Prepulse Facilitation in Schizophrenia Patients

Acoustic prepulse inhibition (PPI) is considered an important biomarker in animal studies of psychosis and a number of psychiatric conditions. Nicotine has been shown to improve acoustic PPI in some animal strains and in humans. However, there is little data on effects of nicotine on acoustic PPI in schizophrenia patients using a double-blind, placebo-controlled study design. The primary aim of the current study was to test the effect of nicotine nasal spray on acoustic PPI in schizophrenia patients. The secondary aim was to test nicotine effect on prepulse facilitation (PPF). The study included 18 schizophrenia patient smokers and 12 healthy control smokers, tested in a double-blind, placebo-controlled, crossover, randomized design immediately after nicotine or saline placebo nasal sprays. PPI was tested using 120 ms prepulse-pulse interval. PPF was tested using 4500 ms prepulse-pulse interval. The results showed a significant main effect of drug on PPI in that nicotine improved PPI compared to placebo (p=0.008) with no drug by diagnosis interaction (p=0.90). Improvement in PPI in response to nicotine was significantly correlated with the baseline severity of clinical symptoms (r=0.59, p=0.02) in patients. There was no significant drug or drug by diagnosis interaction for the 4500 ms prepulse-pulse interval condition. However, nicotine improved inhibition in a subgroup of subjects exhibiting PPF (p=0.002). In conclusion, the findings confirmed that nicotine transiently improves acoustic PPI in schizophrenia patients. Additionally, schizophrenia patients with more clinical symptoms may have benefited more from nicotinic effect on PPI.

Adverse drug reactions

Adverse drug reactions are unwanted reactions to drugs that occur under normal conditions of use, and are probably responsible for 3–5% of all hospital admissions. They are usually classified as Type A (augmented) or Type B (bizarre) reactions. Type A reactions are responsible for 80–90% of all adverse responses to drugs. They are relatively common, well known, and predictable, and have a close temporal relation with drug administration. Although patients vary in their susceptibility, most Type A reactions occur in every patient who is given the drug in sufficient dose. Type B reactions are usually unrelated to the main effects of drugs; they are often dose-independent, uncommon and unpredictable. Although their cause may be obscure, they are sometimes related to genetic predisposition or drug hypersensitivity. In anaesthetic practice, at least three important Type B reactions are directly related to genetic predisposition (malignant hyperthermia, suxamethonium apnoea, hepatic porphyria). Hypersensitivity or allergic responses to drugs depend on immunological factors; there are four types, depending on the mechanism involved. Most severe allergic reactions to drugs are a result of Type I hypersensitivity (anaphylaxis). In anaesthesia, the main aetiological factors are muscle relaxants, antibiotics, latex rubber and chlorhexidine; reactions to these agents may cause hypotension, bronchospasm, facial and laryngeal oedema, or urticaria. Similar effects occur when histamine and other factors are directly released from mast cells by non-immunological mechanisms (anaphylactoid reactions). Finally, drugs that are given during pregnancy may cross the placental barrier and adversely affect the fetus.

ACETYLCHOLINESTERASE INHIBITION AUGMENTS THE SYMPATHETIC NEURAL RESPONSE TO POSTURAL STRESS

Muscle sympathetic nerve activity characteristics of burst frequency, mean burst amplitude and total amplitude were assessed during graded head-up tilt (HUT) (5 min each at 0, 20, 40 and 60°) before and 60 min following either an oral dose of pyridostigmine (60 mg; n = 9) or placebo (n = 5). No drug side effects were noticed. Burst frequency and total amplitude increased during HUT for both groups in both conditions. For the placebo group the increases in burst frequency, mean burst amplitude and total amplitude were not different in the repeated trials. However, following pyridostigmine burst frequency was elevated at rest (P < 0.05) and this elevation was sustained during HUT (main effect; P < 0.003). Similarly, mean burst amplitude (P < 0.004) and total amplitude (P < 0.0001) were elevated following pyridostigmine (main effects of drug). No differences in the neural response to a cold pressor test were observed following the drug or placebo treatment. It was concluded that pyridostigmine treatment, at doses that do not produce cholinergic side effects, augmented the sympathetic postganglionic nerve response to orthostatic stress. (Supported by CSA, NSERC, NAG 9-1844 from NASA, R01 AG12227 and M01 RR10732 from NIH).

Effects of chlorpromazine on lateralization, cued reaction time, and dichotic listening

In a double-blind cross-over design sixteen subjects took 50 mg of chlorpromazine or placebo in tablet form 2 hours prior to completing a dichotic listening and simple reaction time task with and without warnings. In the simple reaction time task, blocks of 80 stimuli were presented to each ear with and without warning cue under drug and placebo conditions. On the dichotic listening task the expected right ear advantage for reporting digits was obtained. While the drug had no main effect on the number of errors, there were more trials on which an ear advantage was present than in the placebo condition. In the reaction time task there were main effects of drug, warning cue and foreperiod: warnings facilitated reaction; chlorpromazine retarded reaction; and reaction times were most facilitated by warning foreperiods in excess of 1200ms. Several findings were of interest: On uncued trials, with placebo, right ear responses were faster than those for stimuli presented to the left ear. Drug also interacted with foreperiod duration. These results were interpreted in the light of Tucker and Williamson’s (1984) review of the role of Pribram and McGuinness’s Arousal and Activation sytems in lateralized behavior.

Spectral analysis of hippocampal EEG in the freely moving rat: Effects of centrally active drugs and relations to evoked potentials

Hippocampal EEG signals derived from chronically were recored before and after administration of implanted electrodes in the freely moving rat centrally acting drugs, and analyzed by power and coherence spectra. Eserine, ether or urethane induced a low frequency (3–6 c/sec) theta power and coherence peak in the immobile rat, which was sensitive to atropine or scopolamine. After phencyclidine, theta that occurred during walking (7–8 c/sec) was virtually abolished by atropine while in the normal rat, absolute theta power was not affected by atropine. The residue spectrum, defined as the EEG spectrum with the theta harmonics removed, was sensitive to centrally acting drugs. Ether, urethane and pentobarbital suppressed fast waves of 50–100 c/sec, and under some conditions, enhanced 15–50 c/sec waves. Eserine enhanced (30–60 c/sec) fast waves during walking while atropine suppressed fast waves and increased irregular slow activity (< 30 c/sec). The main effects of drugs and behavior on the residue spectra and on the average evoked potentials following stimulation of the Schaffer collaterals could be explained by a previously proposed model (Leung 1982) which suggests a continuum of hippocampal ‘activation’ (tonic input) under the various conditions.

Factors of symptom distress. Doctor ratings of anxious neurotic outpatients.

IN A SERIES of related papers by Mattsson et al,1Williams et al,2and Lipman et al,3a Symptom Distress Check List (SCL), developed by Parloff, Frank, and their coworkers,4,5containing items covering the spectrum of common psychoneurotic complaints, was factor-analyzed, employing the self-ratings of more then 1,500 anxious-neurotic outpatients. These Factors were tested for their sensitivity in discriminating pharmacologic and nonpharmacologic influences within the context of a double-blind, placebo-controlled trial of meprobamate in which doctor medication attitudes were experimentally manipulated via role-playing techniques.6 Of the five stable and clinically meaningful factors extracted from the patients' selfratings, Somatization and Fear-Anxiety proved most sensitive to main drug effects, whereas the remaining three factors—General Neurotic Feelings, Cognitive-Performance Difficulty, and Depression—were more reliably influenced by the interaction of pharmacologic and nonpharmacologic variable in the treatment context.

Effects of amobarbital on discrimination acquisition and reversal.

Thirty-two rats injected with 20 mg/kg amobarbital and 32 given placebo were run 96 trials on a black-white discrimination followed by 160 trials of reversal training. Trials to the discriminanda were equated to provide speed data to the nonrewarded stimulus (S−) as well as to the rewarded stimulus (S+). Half the Ss were changed in drug state at the onset of reversal. The drug did not affect choice behavior or differential start speed to S+ and S− in acquisition although speeds closer to the goal were affected. In contrast, during reversal amobarbital Ss made fewer correct choice responses when compared to placebo Ss and displayed less pronounced differential start speed responding to S+ and S−. In addition to the main drug effect, a change of drug state facilitated reversal.