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Biomedical subjects

R A Frank

Publications and source records attributed to R A Frank.

At least 19 recordsLinked to original sources
PubMed2003

Core biological marker candidates of Alzheimer's disease - perspectives for diagnosis, prediction of outcome and reflection of biological activity.

Alzheimer's disease (AD) is a complex neurodegenerative dementing illness. Over the past few years, however, remarkable advances have taken place in understanding both the genetic and molecular biology with the intracellular processing of amyloid and tau and the changes leading to the pathologic formation of extracellular amyloid plaques and the intraneuronal aggregation of hyperphosphorylated tau into neurofibrillary tangles. This progress in our understanding of the molecular pathology has set the stage for clinically meaningful advances in the development of biomarkers. Emerging diagnostic methods that are based on biochemical and imaging biomarkers of disease specific pathology hold the potential to provide effective measures of natural history (marker of disease that is predictive of outcome), biological activity (such as magnitude and frequency of response correlating with drug potency) and markers of surrogate endpoints (single or composite marker that accounts for clinical benefit of the therapy). Markers of biological activity should be also evaluated regarding their value to reflect disease progression, heterogeneity of the clinical population, for early decision making and characterization of new treatments. We focussed on the current status of core analytes which provide reasonable evidence for association with key mechanisms of pathogenesis or neurodegeneration in AD. In addition, feasibility was important, such as availability of a validated assay for the biological measure in question, with properties that included high precision and reliability of measurement, reagents and standards well described. On this basis we reviewed the body of literature that has examined CSF total tau (t-tau) and beta-amyloid 1-42 (Abeta(1-42)), phosphorylated tau (p-tau) and beta-amyloid-antibodies as diagnostic tests for AD versus clinically representative comparison groups. Measurement of t-tau and Abeta(1-42) in the CSF seems useful to discriminate early and incipient AD from age-associated memory-impairment, depression, and some secondary dementias. First studies showed that measurement of p-tau proteins significantly improves early and differential diagnosis, as well as disease prediction in subjects at risk for AD and comes closest to fulfilling proposed criteria of a biological marker for AD. However, the nature of the majority of reported findings are still preliminary and retrospective. General issues for biomarkers have to be adequately addressed, such as sensitivity of the method, frequency of assessments, stability of the method, standardization of methods and dynamic range. There is still a partial lack of comparison patient populations that must be addressed in future studies. International dementia networks have been recently established to advance the establishment of core biomarker candidates of AD as potential surrogate endpoints for clinical trials and their clinical use for predictive and diagnostic purposes.

Alzheimer Disease↗
PubMed2001

Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716.

BACKGROUND: SR141716, a recently developed CB1 cannabinoid receptor antagonist, blocks acute effects of Delta-9-tetrahydrocannabinol (THC) and other CB1 cannabinoid agonists in vitro and in animals. These findings suggest that CB1 receptors mediate many of the effects of marijuana, but this has not been evaluated in humans. METHODS: Sixty-three healthy men with a history of marijuana use were randomly assigned to receive oral SR141716 or a placebo in an escalating dose (1, 3, 10, 30, and 90 mg) design. Each subject smoked an active (2.64% THC) or placebo marijuana cigarette 2 hours later. Psychological effects associated with marijuana intoxication and heart rate were measured before and after antagonist and marijuana administration. RESULTS: Single oral doses of SR141716 produced a significant dose-dependent blockade of marijuana-induced subjective intoxication and tachycardia. The 90-mg dose produced 38% to 43% reductions in visual analog scale ratings of "How high do you feel now?" "How stoned on marijuana are you now?" and "How strong is the drug effect you feel now?" and produced a 59% reduction in heart rate. SR141716 alone produced no significant physiological or psychological effects and did not affect peak THC plasma concentration or the area under the time x concentration curve. SR141716 was well tolerated by all subjects. CONCLUSIONS: SR141716 blocked acute psychological and physiological effects of smoked marijuana without altering THC pharmacokinetics. These findings confirm, for the first time in humans, the central role of CB1 receptors in mediating the effects of marijuana.

Administration, Oral↗
PubMed2001

Left ventricular apex to descending aorta valved conduit: description of transthoracic and transesophageal echocardiographic findings in four cases.

Patients with critical aortic stenosis and a "porcelain" aorta are at an increased risk for complications with aortic cross-clamping during valve replacement. To our knowledge, this is the first report of both transthoracic and transesophageal echocardiographic findings of the left ventricle to the descending aorta (LVDA) valved conduit. We present results of four patients in whom this procedure was performed for critical aortic stenosis, who also had a porcelain aorta. "Normal" echo and Doppler findings, along with those of development of a regurgitant valve within the conduit, are presented.

Aorta, Thoracic↗
PubMed2000

Biodistribution of [18F] SR144385 and [18F] SR147963: selective radioligands for positron emission tomographic studies of brain cannabinoid receptors.

ABSTRACT. [(18)F] SR144385 and [(18)F] SR147963 were synthesized in a multistep reaction in which fluorine-18 was introduced by nucleophilic halogen displacement on a bromo precursor. The fluorine-18-labeled intermediate was deprotected and coupled with the appropriate alkyl amine to give the final products. Both radioligands had appropriate regional brain distribution for cannabinoid receptors with a target to nontarget ratio of 1.7 for [(18)F] SR147963 and 2.5 for [(18)F] SR144385 at 60 and 90 min postinjection, respectively. The uptake of both tracers was blocked with a 1 mg/kg dose of SR141716A.

Administration, Inhalation↗
PubMed1999

Assessing food neophobia: the role of stimulus familiarity.

The present study assesses the effects of food familiarity on food ratings of neophobics and neophilics by having them sample and evaluate familiar and novel foods. Level of neophobia was assessed using the Food Neophobia Scale (FNS). Participants rated their familiarity with each food, their willingness to try the foods and expected liking for the foods, as well as their actual liking for the foods after they were sampled. Willingness to try the foods again in the future, and the amount of food sampled were also assessed. Evaluations of the foods were more positive for familiar vs. unfamiliar foods across all study participants. The responses of neophobics and neophilics were similar for familiar foods, but differed when the foods were unfamiliar, with neophobics making more negative evaluations. Neophobics and neophilics differed least in their liking ratings of the stimuli that were made after the foods were actually sampled, and differed most in their ratings of willingness to try the foods. It is concluded that neophobics have different expectancies about unfamiliar foods, and that these expectancies influence food sampling and rating behaviors. The neophobic's negative attitude toward an unfamiliar food may be ameliorated, but is not eliminated, once sensory information about the food is obtained.

Adolescent↗
PubMed1998

Food neophobia, odor evaluation and exploratory sniffing behavior.

Past research has shown that people who avoid new foods (neophobics) and people who approach new foods (neophilics) differ in their sensory ratings of food and odor stimuli. The possible role of sampling behaviors in these differences was assessed in two studies. Participants completed neophobia surveys, then rated the pleasantness of odors while wearing a device that measured sniffing behavior. Neophobics rated the odors as less pleasant and sniffed them less vigorously in both studies. The results of these studies provide further evidence for differences in the way that neophobics and neophilics respond to novel, food-like stimuli. Neophobia influences willingness to try novel foods, expected liking for these foods, food-associated sampling behaviors and post-sampling ratings of food-like stimuli. It is proposed that the responses of neophobics and neophilics will differ when little information about the sensory properties of foods are available, and that these differences will moderate as sensory information is acquired.

Adolescent↗
PubMed1998

Mixed D2/5-HT2A antagonism of cocaine-induced facilitation of brain stimulation reward.

Previous behavioral, neurochemical and neurophysiological experiments have shown that selective 5-HT2A and mixed D2/5-HT2A antagonists can attenuate some, but not all, responses to amphetamine. The generality of these findings were determined in the present experiment by assessing the effect of mixed D2/5-HT2A antagonists on cocaine-induced facilitation of ventral tegmental area self-stimulation in rats. Although amphetamine and cocaine influence activity in monoaminergic neurons through different mechanisms, our previous research has shown that selective D2 and 5-HT2A antagonists have similar effects on behavioral responses to these psychostimulants. Therefore, we expected a similar pattern of results using mixed D2/5-HT2A antagonists. As shown previously, cocaine decreased self-stimulation threshold in a dose-dependent manner. Haloperidol and the mixed D2/5-HT2A antagonists risperidone and MDL 28, 133A antagonized cocaine-induced facilitation of self-stimulation, but only at doses that increased baseline self-stimulation threshold. There was a significant correlation (r = 0.87, p < 0.001) between antagonist-induced change in baseline threshold and attenuation of cocaine's effect on threshold. Taken together, the results of this and previous experiments support the importance of D2 receptors in the mechanisms of brain stimulation reward. 5-HT2A receptors appear not to be involved in mediation of both brain stimulation reward and amphetamine- and cocaine-induced facilitation of brain stimulation reward.

Animals↗
PubMed1997

Mixed D2/5-HT2 antagonism differentially affects apomorphine- and amphetamine-induced stereotyped behavior.

Evidence supports the hypothesis that psychostimulant stereotypy is mediated through postsynaptic dopamine receptors. Given the recent findings of behavioral, neurochemical and electrophysiological studies showing 5-HT2 modulation of dopamine systems, a series of experiments were undertaken to assess the ability of D2 and 5-HT2 antagonists to reverse apomorphine and amphetamine stereotypy in the rat. Haloperidol reduced stereotyped behavior induced by d-amphetamine (50% reduction with 0.162 mg/kg) and apomorphine (50% reduction with 0.112 mg/kg) MDL 28,133A, a mixed D2/5-HT2 antagonist, also reduced stereotypy in the apomorphine group (50% reduction with 3.89 mg/kg) but was much less effective in antagonizing the effects of d-amphetamine (not even a 25% reduction with 9.0 mg/kg). MDL 100,907, a selective 5-HT2 antagonist, was ineffective at reducing stereotyped behavior induced by either stimulant. Thus, 5-HT2 modulation of dopaminergic activity was not demonstrated in the case of psychostimulant stereotypy. Furthermore, 5-HT2 antagonism did not induce stereotypy, as has been proposed in some models. These findings provide further support for the hypothesis that antipsychotic medications with high affinity for 5-HT2 receptors do not interfere with the regulation of the nigrostriatal dopaminergic system and, therefore, would be less likely to produce extrapyramidal side effects.

Amphetamine↗
PubMed1996

Reversal of amphetamine-induced behaviours by MDL 100,907, a selective 5-HT2A antagonist.

MDL 100,907 is a potent and selective antagonist of the 5-HT2A receptor which, unlike other antagonists at this receptor, has little affinity for the 5-HT2C receptor. We have investigated the antipsychotic potential of MDL 100,907 by examining its ability to antagonise different behavioural effects of amphetamine in rats. MDL 100,907 reversed the locomotor stimulant effects of amphetamine in rats without itself having any effect on locomotor activity. It also antagonised the disruptive effects of amphetamine on the development of latent inhibition. In contrast, MDL 100,907 had no effect on the discriminative stimulus properties of amphetamine, nor did it affect the ability of amphetamine to reduce the threshold required to sustain rewarding brain stimulation in the ventral tegmental area. This profile is different from that of typical and atypical neuroleptics, and also from other 5-HT2 receptor antagonists, which lack the selectivity of MDL 100,907. These results suggest that MDL 100,907 may have a unique interaction with dopaminergic systems and support the further development of selective 5-HT2 receptor antagonists as a novel therapeutic strategy for schizophrenia.

Amphetamine↗
PubMed1996

Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a potent 5-HT2A antagonist with a favorable CNS safety profile.

In preclinical studies, [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4- piperidinemethanol] [formula: see text] (MDL 100,907), a putative atypical antipsychotic, was characterized in vitro as a potent and selective ligand for the serotonin2A (5-HT2A) receptor and was evaluated in vitro and in vivo as a potent 5-HT2A receptor antagonist. Furthermore, MDL 100,907's potential CNS safety profile and selectivity as a potential antipsychotic agent were evaluated and compared with benchmark compounds. MDL 100,907 demonstrated low nanomolar or subnanomolar binding in vitro at the 5-HT2A receptor and showed a > 100-fold separation from all other receptors measured. MDL 100,907 had subnanomolar potency as a 5-HT2A antagonist in vitro in reversing 5-HT-stimulated inositol phosphate accumulation in NIH 3T3 cells transfected with the rat 5-HT2A receptor. In vivo, MDL 100,907 potently inhibited 5-methoxy-N, N-dimethyltryptamine-induced head twitches in mice or 5-hydroxytryptophan-induced head twitches in rats. In vivo functional tests in mice revealed a > 500-fold separation between doses that produced 5-HT2A antagonism and doses that produced alpha 1-adrenergic or striatal D2 antagonism. Using inhibition of D-amphetamine-stimulated locomotion in mice as a measure of potential antipsychotic efficacy, MDL 100,907 showed a superior CNS safety index relative to the reference compounds, haloperidol, clozapine, risperidone, ritanserin, and amperozide, in each of five tests for side effect potential, including measures of ataxia, general depressant effects, alpha 1-adrenergic antagonism, striatal D2 receptor antagonism, and muscle relaxation. MDL 100,907 did not antagonize apomorphine-induced stereotypes in rats, suggesting that it potentially lacks extrapyramidal side effect liability. MDL 100,907 showed selectivity as a potential antipsychotic in that it lacked consistent activity in selected rodent models of anticonvulsant, antidepressant, analgesic, or anxiolytic activity. In summary, these preclinical data indicate that MDL 100,907 is a potent and selective ligand at the 5-HT2A receptor. MDL 100,907's potent 5-HT2A antagonist activity might account for its activity in preclinical models of antipsychotic potential. Ongoing clinical evaluation with MDL 100,907 will test the hypothesis that 5-HT2A receptor antagonism is sufficient for antipsychotic activity in humans.

Animals↗
PubMed1995

The contribution of psychological and sensory factors to food preference patterns as measured by the Food Attitudes Survey (FAS).

The relationship between food preference patterns and several psychological and sensory variables was assessed using the Food Attitudes Survey (FAS). Previous research with the FAS, which consists of preference ratings for a variety of common, unusual and fictitious foods, showed that it provides both reliable and valid information about individual differences in food preferences and attitudes (Frank & van der Klaauw, 1994). In the studies reported here, significant correlations were found between preferences for a variety of activities (as measured by the Activity Attitudes Survey or ACT) and liking for and willingness to try foods, It was also found that individuals who report that they are unwilling to try many foods are low in general sensation seeking, and that odor pleasantness ratings significantly correlate with liking for and willingness to try foods. No associations were found between FAS performance and general phobic tendencies, optimism/pessimism or disordered eating. Multiple regression analysis revealed that responses on the ACT, sensation seeking scale, a 20-item food and eating questionnaire and odor pleasantness judgments could account for from 41 to 65% of the variance in food likes, dislikes and willingness to try foods. It was concluded that personality and sensory factors contribute to pattern of responding on the FAS, and that FAS response patterns provide an index of both attitudes toward foods and general openness to experiences and activities.

Adolescent↗
PubMed1995

Mixed D2/5-HT2A antagonism of amphetamine-induced facilitation of brain stimulation reward.

Recent experiments have demonstrated that 5-HT2A antagonists can modify electrophysiological, neurochemical, and behavioral responses to psychostimulants. These findings led to an interest in using 5-HT2A antagonists to block the effects of psychostimulants on brain reward mechanisms. The present experiments assessed the ability of mixed D2/5-HT2A antagonists to reverse amphetamine-induced facilitation of self-stimulation. The D2/5-HT2A antagonists MDL 28,133A and risperidone attenuated the effects of cocaine and amphetamine, but only at antagonist doses that elevated baseline self-stimulation thresholds. A comparison of the effects of the mixed antagonists to those of haloperidol and eticlopride revealed that all four antagonists produced similar anti-stimulant effects when the influence of the drugs on baseline responding was considered. The D2 activity of the antagonists appears to account for their ability to reduce the effects of psychostimulants on self-stimulation. 5-HT2A antagonism makes a negligible contribution to the anti-amphetamine effects.

Amphetamine↗
PubMed1994

The contribution of chemosensory factors to individual differences in reported food preferences.

A new psychometric instrument, the Food Attitude Survey (FAS), was developed to identify individual differences in general response patterns or attitudes toward foods. The FAS consists of food preference ratings (like, neutral, dislike, never tried but would try, never tried and won't try) for 455 foods and beverages, including some unusual and fictitious foods. In addition, it includes a 20-item questionnaire concerning attitudes toward food and eating. Using the FAS, people who reported liking an unusually high number of foods (likers) were compared to those who disliked many foods (dislikers) and those who were unwilling to try many foods (won't tryers). The characteristics of the three groups were evaluated using several sensory tests to assess the contribution of perceptual factors to individual differences in food attitudes and preferences. Intensity and hedonic ratings of olfactory stimuli were generally lower for the won't tryers than for the likers, with dislikers in between. In addition, the ideal taste intensities of likers were higher than those of dislikers or won't tryers. On the basis of these initial studies, it is concluded that the FAS provides a reliable index of individual differences in food preference patterns, making the FAS a useful tool for investigating the "personality of eating". The present studies also provide evidence that differences in chemosensory responses may be associated with biases toward food acceptance or rejection.

Adult↗
PubMed1994

Reoperative coronary artery bypass grafting.

In recent years reoperative coronary artery bypass surgery has become increasingly more commonplace. This article reviews the current status of this procedure with regard to patient population, risk factors, and long-term follow-up. Important aspects of the specific technical considerations involved in reoperative surgery are also reviewed and evaluated.

Coronary Artery Bypass↗
PubMed1994

Determinants of stability in the perception of subjective contours.

The present study constituted an initial experimental effort to examine the fragmentation characteristics of subjective contours within the photopic and upper scotopic ranges of illumination. Four stimulus factors known to influence the visibility of subjective contours-target luminance, inducing area size and contrast, and contour orientation--were examined. Results indicated that subjective contours are indeed unstable perceptual phenomena. On the average, fragmentation or fading occurred after only 15 sec of observation, and some form of stimulus outage was present for 28% of the viewing time of each stimulus. Fragmentation latency was significantly shorter and total time in fragmentation longer for diamond than for square contours, and total time in fragmentation varied inversely with inducing-area size. Fragmentation tended to occur in whole units rather than in isolated elements, a result reminiscent of the fading of real contours under impoverished viewing conditions.

Form Perception↗