Rosa Maria Antonijoan

Apathy in Parkinson's Disease: Neurophysiological Evidence of Impaired Incentive Processing

Apathy is one of the most common and debilitating nonmotor manifestations of Parkinsons disease (PD) and is characterized by diminished motivation, decreased goal-directed behavior, and flattened affect. Despite its high prevalence, its underlying mechanisms are still poorly understood, having been associated with executive dysfunction, and impaired emotional processing and decision making. Apathy, as a syndrome, has recently been associated with reduced activation in the ventral striatum, suggesting that early- to middle-stage Parkinsons disease patients with this manifestation may have a compromised mesocorticolimbic dopaminergic pathway and impaired incentive processing. To test this hypothesis, we measured the amplitude of the feedback-related negativity, an event-related brain potential associated with performance outcome valence, following monetary gains and losses in human PD patients (12 women) and healthy controls (6 women) performing a gambling task. Early- to middle-stage PD patients presenting clinically meaningful symptoms of apathy were compared with nonapathetic PD patients and healthy controls. Patients with cognitive impairment, depression, and other psychiatric disturbances were excluded. Results showed that the amplitude of the feedback-related negativity, measured as the difference wave in the event-related brain potential between gains and losses, was significantly reduced in PD patients with apathy compared with nonapathetic patients and healthy controls. These findings indicate impaired incentive processing and suggest a compromised mesocorticolimbic pathway in cognitively intact PD patients with apathy.

Comparison of peripheral and central effects of single and repeated oral dose administrations of bilastine, a new H1 antihistamine: a dose-range study in healthy volunteers with hydroxyzine and placebo as control treatments.

Peripheral anti-H1 and central nervous system (CNS) activities after single (day 1) and repeated (day 7) administrations of increasing doses of bilastine (BIL) were assessed in 20 healthy volunteers throughout a crossover, randomized, double-blind, placebo (PLA)-controlled study. Repeated doses of BIL 20, 40, or 80 mg and hydroxyzine 25 mg (HYD) as positive standard were administered on 7 consecutive days. Before and at several time points after drug intake, skin reactivity to the intradermal injection of histamine, objective tests of psychomotor performance, and subjective mood scales were evaluated. All active treatments led to a significant and similar reduction in the wheal reaction in relation to PLA after both the single (P < 0.001) and repeated administrations (P < 0.001). No delay was observed in the onset of its peripheral activity after the first dose of BIL as compared with HYD. No tolerance or sensitization was seen when comparing acute and repetitive assessments. Central nervous system effects showed that HYD induced the greatest psychomotor impairment (P < 0.05). Repeated HYD intake showed a lower number of significant alterations in comparison to acute administration. Bilastine 80 mg also showed some impairment (P < 0.05). Subjectively, the only active treatment that could not be differentiated from PLA was BIL 20 mg. Hydroxyzine 25 mg showed the greatest differentiation (P < 0.01). A clear dissociation between peripheral anti-H1 and CNS activity was found after BIL treatment. Significant and sustained peripheral H1-blocking effects were observed after both single and repeated administrations of the therapeutic dose of 20 mg BIL. The 40-mg dose of BIL produced subjective report of sedation, whereas unwanted objective CNS side effects were observed only with the 80-mg dose.

A double-blind crossover, placebo-controlled study of the adenosine A2A antagonist theophylline in Parkinson's disease.

Blockade of the adenosine A2A receptor potentiates the effects of levodopa in experimental animals and may offer a novel nondopaminergic target for drug therapy in Parkinsons disease (PD). Open-label trials suggest that the nonspecific adenosine antagonist theophylline improves parkinsonian symptoms and increases ON time in advanced patients with PD. In a double-blind, crossover, placebo-controlled trial, the authors investigated the ability of stable plasma levels of theophylline (between 10–20 &mgr;g/mL after 15 days of treatment) to modulate the long-duration response and the short-duration response of levodopa in 10 patients with PD. Although theophylline induced a longer duration of the effect of levodopa in all Unified Parkinsons Disease Rating Scale variables considered, including dyskinesias, maximal levodopa-induced improvement and the duration of the effect of levodopa did not differ significantly from placebo. Only the secondary variable “akinesia” showed a statistical tendency to a more prolonged beneficial response with theophylline during an acute levodopa test (short-duration response), and tremor worsened with theophylline during levodopa withdrawal (long-duration response). No differences were observed during the subacute course of study medication added to levodopa. During this exploratory study, the effects of theophylline were not strong enough to potentiate clearly the antiparkinsonian action of levodopa or to increase ON time in patients with advanced PD.

Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans

Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus β-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimentally. Here we wished to study the contribution of the 5-HT2A receptor to the neurophysiological and psychological effects of ayahuasca in humans. We measured drug-induced changes in spontaneous brain oscillations and subjective effects in a double-blind randomized placebo-controlled study involving the oral administration of ayahuasca (0.75mg DMT/kg body weight) and the 5-HT2A antagonist ketanserin (40mg). Twelve healthy, experienced psychedelic users (5 females) participated in four experimental sessions in which they received the following drug combinations: placebo+placebo, placebo+ayahuasca, ketanserin+placebo and ketanserin+ayahuasca. Ayahuasca induced EEG power decreases in the delta, theta and alpha frequency bands. Current density in alpha-band oscillations in parietal and occipital cortex was inversely correlated with the intensity of visual imagery induced by ayahuasca. Pretreatment with ketanserin inhibited neurophysiological modifications, reduced the correlation between alpha and visual effects, and attenuated the intensity of the subjective experience. These findings suggest that despite the chemical complexity of ayahuasca, 5-HT2A activation plays a key role in the neurophysiological and visual effects of ayahuasca in humans.

Bioavailability and pharmacokinetics of a new low molecular weight heparin (RO-11)—A three way cross-over study in healthy volunteers

This study reports on the bioavailability and pharmaco kinetics of a new low molecular weight heparin (RO-11), with a mean molecular weight of 3,600-3,800 daltons. It was administered to 12 healthy individuals in an open, cross-over study. Each subject was randomly assigned to three experimental treatments: a) 30 mg by subcutaneous route, b) 60 mg subcutaneously and c) 60 mg intravenously, leaving a wash-out period of one week between treatments. The pharmacokinetic profile was calculated by means of the anti-FXa effect, measured on serial samples taken before and during the 24 h period after each treatment. The effects of the drug on global coagulation tests, Antithrombin-III levels, tissue-factor pathway inhibitor activity and anti-FIIa activity were also assessed. After the intravenous injection, a maximal anti-FXa effect of 1.30 +/- 0.18 IU/ml was measured at 0.05 h and was not measurable after 12 h. After the subcutaneous injection of 30 and 60 mg, the maximal anti-FXa effect (0.34 +/- 0.08 IU/ml and 0.54 +/- 0.06 IU/ml) was reached after 2-4 h, and was not measurable after 12-18 h. The magnitude of this effect was dose-dependent and the absorption and elimination processes followed a first-order pattern for every dose and route. RO-11 showed a biological half-life of about 5 h and a high subcutaneous bioavailability (96%).

Salvinorin-A Induces Intense Dissociative Effects, Blocking External Sensory Perception and Modulating Interoception and Sense of Body Ownership in Humans

Background: Salvinorin-A is a terpene with agonist properties at the kappa-opioid receptor, the binding site of endogenous dynorphins. Salvinorin-A is found in Salvia divinorum, a psychoactive plant traditionally used by the Mazatec people of Oaxaca, Mexico, for medicinal and spiritual purposes. Previous studies with the plant and salvinorin-A have reported psychedelic-like changes in perception, but also unusual changes in body awareness and detachment from external reality. Here we comprehensively studied the profiles of subjective effects of increasing doses of salvinorin-A in healthy volunteers, with a special emphasis on interoception. Methods: A placebo and three increasing doses of vaporized salvinorin-A (0.25, 0.50, and 1mg) were administered to eight healthy volunteers with previous experience in the use of psychedelics. Drug effects were assessed using a battery of questionnaires that included, among others, the Hallucinogen Rating Scale, the Altered States of Consciousness, and a new instrument that evaluates different aspects of body awareness: the Multidimensional Assessment for Interoceptive Awareness. Results: Salvinorin-A led to a disconnection from external reality, induced elaborate visions and auditory phenomena, and modified interoception. The lower doses increased somatic sensations, but the highest dose led to a sense of a complete loss of contact with the body. Conclusions: Salvinorin-A induced intense psychotropic effects characterized by a dose-dependent gating of external audio-visual information and an inverted-U dose-response effect on body awareness. These results suggest a prominent role for the kappa opioid receptor in the regulation of sensory perception, interoception, and the sense of body ownership in humans.

Acute effects of ayahuasca on neuropsychological performance: differences in executive function between experienced and occasional users

BackgroundAyahuasca, a South American psychotropic plant tea containing the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine, has been shown to increase regional cerebral blood flow in prefrontal brain regions after acute administration to humans. Despite interactions at this level, neuropsychological studies have not found cognitive deficits in abstinent long-term users.ObjectivesHere, we wished to investigate the effects of acute ayahuasca intake on neuropsychological performance, specifically on working memory and executive function.MethodsTwenty-four ayahuasca users (11 long-term experienced users and 13 occasional users) were assessed in their habitual setting using the Stroop, Sternberg, and Tower of London tasks prior to and following ayahuasca intake.ResultsErrors in the Sternberg task increased, whereas reaction times in the Stroop task decreased and accuracy was maintained for the whole sample following ayahuasca intake. Interestingly, results in the Tower of London showed significantly increased execution and resolution times and number of movements for the occasional but not the experienced users. Additionally, a correlation analysis including all subjects showed that impaired performance in the Tower of London was inversely correlated with lifetime ayahuasca use.ConclusionsAcute ayahuasca administration impaired working memory but decreased stimulus–response interference. Interestingly, detrimental effects on higher cognition were only observed in the less experienced group. Rather than leading to increased impairment, greater prior exposure to ayahuasca was associated with reduced incapacitation. Compensatory or neuromodulatory effects associated with long-term ayahuasca intake could underlie preserved executive function in experienced users.

Pharmacokinetics of the somatostatin analog lanreotide in patients with severe chronic renal insufficiency

To characterize the pharmacokinetic profile of the somatostatin analog lanreotide in patients with severe chronic renal insufficiency.

Efficacy of ebastine, cetirizine, and loratadine in histamine cutaneous challenges

BACKGROUND Few studies have compared the antihistaminic effect of ebastine at 20 mg/day (maximal recommended daily dose) with the effect found for other antihistamines in human pharmacologic models. OBJECTIVE To compare the inhibition of the histamine-induced skin reaction produced by ebastine (20 mg/day) with that produced by cetirizine (10 mg/day), loratadine (10 mg/day), or placebo in a double-blind, randomized, crossover, placebo-controlled clinical trial. METHODS Twenty volunteers (10 men and 10 women) received the four treatments once daily for 7 days, with a mean 7-day washout period between treatments. Three intradermal histamine challenges (0.05 mL of a 100 microg/mL histamine solution at 4, 8, and 24 hours after drug administration) were performed at baseline, day 1 (single dose), and day 7 (multiple doses). Wheal and flare areas were measured after 15 minutes. RESULTS All treatments yielded significant reductions of histamine-induced wheal in comparison to placebo (P < 0.001). Analysis of covariance revealed significant differences between treatments (P < 0.05). Ebastine had a significantly greater antihistaminic effect than did cetirizine or loratadine, except at 4 hours after a single dose versus cetirizine. Further, the effect of cetirizine was similar with single or multiple doses after both 4 and 24 hours, whereas the effect of ebastine showed significant increases in wheal reduction with multiple doses (P < 0.05). No serious adverse events or withdrawals occurred during the study. CONCLUSION This study shows that ebastine in a 20-mg dose is an effective once-daily antihistamine. Superior efficacy was found in comparison to cetirizine (10 mg) or loratadine (10 mg) on the overall skin wheal response after single and multiple doses.

Pharmacokinetic and safety profile of rupatadine when coadministered with azithromycin at steady-state levels: a randomized, open-label, two-way, crossover, Phase I study

BACKGROUND Rupatadine is an oral active antihistamine and platelet-activating factor antagonist indicated for the management of allergic rhinitis and chronic urticaria in Europe. OBJECTIVE The purpose of this study was to describe the effect of the concomitant administration of azithromycin and rupatadine on the pharmacokinetics of rupatadine and its metabolites after repeated doses. METHODS This was a multiple-dose, randomized, open-label, 2-way, crossover, Phase I study in which healthy male and female volunteers received rupatadine 10 mg once a day for 6 days either alone or with azithromycin 500 mg on day 2 and 250 mg from day 3 to day 6. Treatments were administered after a fasting period of 10 hours with 240 mL of water, and fasting conditions were kept until 3 hours postmedication. A washout period of at least 21 days between the 2 active periods was observed. Blood samples were collected and plasma concentrations of rupatadine and its metabolites desloratadine and 3-hydroxydesloratadine were determined by liquid chromatography tandem mass spectrometry. Tolerability was based on the recording of adverse events (AEs), physical examination, electrocardiograms, and laboratory screen controls at baseline and the final study visit. RESULTS Twenty-four healthy volunteers (15 males, 9 females; mean [SD] age, 25.67 [5.58] years; weight, 65.96 [8.57] kg) completed the study. Except for maximum observed concentration during a dosing interval (Cmax,ss) of 3-hydroxydesloratadine, on average, there were no statistically significant differences in mean plasma concentrations in any of the main pharmacokinetic parameters of rupatadine, desloratadine, and 3-hydroxydesloratadine when administered in combination with azithromycin or alone. The Cmax,ss ratio was 111 (90% CI, 91-136) and area under the plasma concentration-time curve during a dosing interval (AUC0-tau) ratio had a value of 103 (90% CI, 91-117). The corresponding ratios for the rupatadine metabolites were 109 (90% CI, 100-120) for Cmax,ss and 103 (90% CI, 96-110) for AUC0-tau for desloratadine and 109 (90% CI, 103-115) for Cmax,ss and 104 (90% CI, 100-108) for AUC0-tau for 3-hydroxydesloratadine. Point estimates for Cmax,ss ratios using paired data were 111% for rupatadine, 109% for desloratadine, and 109% for 3-hydroxydesloratadine. The 90% CIs were included in the interval 80% to 125% for desloratadine and 3-hydroxydesloratadine, whereas 90% CI for rupatadine was shifted to the right of the interval used for comparing bioavailability of the drugs. A total of 5 subjects reported 9 AEs; 5 of these were thought to be related to the drug administration and all were categorized as mild or moderate. The reported AEs were somnolence (1/24 in the rupatadine group and 1/24 in the rupatadine plus azithromycin group), diarrhea (1/24 in the rupatadine plus azithromycin group), and gastric discomfort (2/24 in the rupatadine plus azithromycin group). Four AEs were considered not to be related (2 episodes of headache, 1 anemia, 1 cheilitis). All were resolved spontaneously. No serious AEs were reported. CONCLUSIONS The results of this study in these healthy volunteers found no significant differences in pharmacokinetic parameters other than Cmax,ss of 3-hydroxydesloratadine between rupatadine 10 mg administered alone or with azithromycin 500 mg on day 2 and 250 mg from day 3 to day 6. The administration of rupatadine compared with rupatadine plus azithromycin met the regulatory definition of bioequivalence in terms of exposure and rate parameters; however, Cmax,ss of rupatadine was outside the conventional confidence interval.