Impact of point-of-care testing for CYP2C19 on platelet inhibition in patients with acute coronary syndrome and early dual antiplatelet therapy in the emergency setting

Aims

Only limited data exist about the role of point of care CYP2C19 testing in the acute setting in the early phase of acute coronary syndromes (ACS). Therefore, the present study was designed to investigate the impact of CYP2C19 loss-of–function point-of-care (POC) genotyping in patients presenting with acute coronary syndromes (ACS) and treated with dual antiplatelet therapy in the emergency setting.

Methods and Results

137 subjects with ACS scheduled for percutaneous coronary intervention were consecutively enrolled. Pre- and on-treatment platelet aggregation was assessed by multiple electrode aggregometry (MEA) after stimulation with adenosine diphosphate (ADP). Patients were loaded according to current guideline adherent indications and contraindications for use of P2Y₁₂ inhibitors in ACS. POC genotyping for CYP2C19*2 was performed in the emergency room after obtaining a buccal swab using the Spartan RX CYP2C19 system and obtaining patient’s informed consent. Prasugrel and ticagrelor treated patients had significantly lower PR compared to clopidogrel-treated patients. The benefits of prasugrel and ticagrelor compared to clopidogrel treated patients in terms of platelet inhibition were more pronounced in CYP2C19*2 carriers. Non-carriers showed similar inhibition regardless of particular P2Y₁₂ inhibitor treatment. Statistical analyses adjusting for factors associated with response (e.g. smoking) revealed that CYP2C19*2 allele carrier status and loading with different type of P2Y12 receptor blockers were significant predictors of on-treatment platelet reactivity in the early phase of ACS.

Conclusion

The results of this pilot study of treatment of patients in the early phase of ACS indicate that CYP2C19*2 POC genotyping might help to identify patients at risk with poor response to clopidogrel treatment, thereby benefiting from reloading and switching to alternative P2Y₁₂ receptor inhibition.     

Deep brain stimulation of the ventral intermediate nucleus in patients with essential tremor: stimulation below intercommissural line is more efficient but equally effective as stimulation above

Background

The posterior subthalamic area (PSA), ventral to the intercommissural line (ICL) and the ventral intermediate nucleus (VIM), has been suggested as a promising target for deep brain stimulation (DBS) in patients suffering from essential tremor (ET). In this study the clinical benefit of VIM and PSA DBS on postural tremor suppression was systematically evaluated in a two step approach with a 3D ultrasound kinematic analysis tool.

Methods

We defined the exact position of 40 VIM-DBS-electrodes from 21 ET patients. In a first experiment with a subgroup of electrodes we subsequently activated a thalamic and a contact below ICL (sub-ICL) with equal parameter settings for within subject comparison. In a second step, we divided all electrodes into two groups, i.e. one group with activated thalamic and the other group with activated contacts below ICL and performed a group comparison under patients' individual stimulation parameters. Here, the corrected amplitude required for tremor suppression was analyzed separately for both groups.

Results

Within subject comparison with equal parameter settings revealed a significant improvement of sub-ICL compared to thalamic stimulation. In contrast, group comparison under patients' individual stimulation did not show any significant difference in tremor suppression between VIM and PSA DBS. Although higher corrected stimulation amplitude was needed in the thalamic group this difference was not significant.

Conclusion

The data suggest that sub-ICL stimulation may be more efficient compared to thalamic stimulation but equally effective when patients' individual stimulation parameters are used.     

Bone mineral density in adult patients treated with various antiepileptic drugs

There is considerable evidence suggesting, that older antiepileptic drugs (AEDs) and some of the newer ones decrease bone mineral density (BMD). However, there is only limited and conflicting data concerning the effect of levetiracetam on BMD. In this cross-sectional study we analysed data from 168 adult consecutive outpatients treated with AEDs for more than 2 years, and who underwent measurement of the BMD. We compared the incidence of decreased BMD among the patients treated with 6 different AEDs: carbamazepine (CBZ), oxcarbazepine (OXC), valproic acid (VPA), lamotrigine (LTG), topiramate (TPM) and levetiracetam (LEV). Among the patients on monotherapy, reduced BMD was present significantly most often in patients treated with LEV and those treated with OXC. In the group of patients on polytherapy there was no significant difference in the incidence of low BMD among patients treated with various AEDs. Our data suggest that patients on long-term treatment with LEV have a higher risk for affection of bone density.     

Impact of dynamic bottom-up features and top-down control on the visual exploration of moving real-world scenes in hemispatial neglect

Patients with hemispatial neglect are severely impaired in orienting their attention to contralesional hemispace. Although motion is one of the strongest attentional cues in humans, it is still unknown how neglect patients visually explore their moving real-world environment. We therefore recorded eye movements at bedside in 19 patients with hemispatial neglect following acute right hemisphere stroke, 14 right-brain damaged patients without neglect and 21 healthy control subjects. Videos of naturalistic real-world scenes were presented first in a free viewing condition together with static images, and subsequently in a visual search condition. We analyzed number and amplitude of saccades, fixation durations and horizontal fixation distributions. Novel computational tools allowed us to assess the impact of different scene features (static and dynamic contrast, colour, brightness) on patients' gaze. Independent of the different stimulus conditions, neglect patients showed decreased numbers of fixations in contralesional hemispace (ipsilesional fixation bias) and increased fixation durations in ipsilesional hemispace (disengagement deficit). However, in videos left-hemifield fixations of neglect patients landed on regions with particularly high dynamic contrast. Furthermore, dynamic scenes with few salient objects led to a significant reduction of the pathological ipsilesional fixation bias. In visual search, moving targets in the neglected hemifield were more frequently detected than stationary ones. The top-down influence (search instruction) could neither reduce the ipsilesional fixation bias nor the impact of bottom-up features. Our results provide evidence for a strong impact of dynamic bottom-up features on neglect patients' scanning behaviour. They support the neglect model of an attentional priority map in the brain being imbalanced towards ipsilesional hemispace, which can be counterbalanced by strong contralateral motion cues. Taking into account the lack of top-down control in neglect patients, bottom-up stimulation with moving real-world stimuli may be a promising candidate for future neglect rehabilitation schemes.     

Genetic animal models for retinal degeneration

Inherited retinal degenerations are a common cause of blindness in Western countries. A mechanism for most retinal degenerations is still unknown; hence, a suitable treatment for most of these diseases has yet to be found. Before one can rationally design a treatment, it is necessary to understand the pathway from a gene mutation to the phenotype in patients. Animal models are crucial to understand this process and to develop a treatment. Some naturally occurring animal models are known. However, over the past few years, transgenic engineering has allowed the generation of a rapidly growing number of animal models. In this review, we give an overview of the broad variety of genetic animal models for retinal degeneration.     

The effect of cryoprotectants on the physical properties of large liposomes containing sodium diclofenac

Large liposomes (1-10 microm) containing sodium diclofenac were prepared and lyophilized using lactose or mannitol (7.5% in respect to the lipid content) as cryoprotectants. The physical studies of liposomes were performed during 30 days of storage in a dry or resuspended form. Lyophilization of large liposomes and storage in the dry form at 5 degrees C increases their physical stability. Lactose is a cryoprotectant which does not influence changes of properties of liposomes regarding their size, encapsulation efficacy and release rate. Large liposomes lyophilized in the presence of mannitol tend to increase in size and encapsulation efficacy, but the lipid bilayers are stabilized and less permeable to the drug.     

Synthesis and effects on chloroquine susceptibility in Plasmodium falciparum of a series of new dihydroanthracene derivatives

To suggest a mechanism of action for drugs capable to reverse the chloroquine resistance, a new set of 9,10-dihydro-9,10-ethano and ethenoanthracene derivatives was synthesized and compounds were tested with the aim to assess their effect on chloroquine susceptibility in Plasmodium falciparum resistant strains. With respect to this, reversal of resistance and change in drug accumulation were compared. Structure-activity relationship and molecular modeling studies made it possible to define a pharmacophoric moiety for reversal agents and to propose a putative model of interaction with some selected amino acids.     

Risk factors for ischemic heart disease and glycosaminoglycans (GAG's) in plasma in atherosclerosis obliterans

GAGs (glycosoaminoglycans) derive from damaged artery endothelium cells. Theoretically their concentration could be used to measure the level of atherosclerosis process. The aim of the study was to estimate the concentration of glucosamine and galactosamine in plasma in patients with AO in comparison to the main risk factors of CHD: smoking, hyperlipidemia, hypertension. Investigated group: the subject of the study were 35 men and 26 women suffering from AO. The control group comprised 20 men and 28 women. People from both groups were 36-65 years old. The concentration of glucosamine and galactosamine were determined by automatic amino acid analyzer LC 6001 Biotronic. The lipids in plasma were determined by conventional methods. Results 100% of men and 81% of women with AO were smokers to compare 70% and 17% in the control group. Systolic blood pressure in men with AO was 134 +/- 13 mm Hg and in women 136 +/- 16 mm Hg. In the control groups they were respectively 122 +/- 10 mm Hg and 124 +/- 10 mm Hg. The difference between the groups is statistically significant. Diastolic and systolic pressures in women with AO were higher then in the control group. In men with AO systolic pressure, but not diastolic pressure, was higher than in the control group. It was observed that in women with AO the concentration of total cholesterol, LDL-chol, apo B in serum, apo B in LDL, TG, TC-HDL-chol/HDL-chol, LDL/HDL were higher, HDL-chol was lower in comparison with the control group. In men with AO total cholesterol, LDL-chol/HDL-chol and TC-HDL-chol/HDL-chol were higher then in the control group, HDL-chol was lower. 80% of women and 74% of men with AO suffered from hyperlipidemia compared with 36% and 60% in the control group respectively. Mixed hyperlipidemia was the most important factor differentiating patients with AO and the control group, when compared to other types of hyperlipidemia. The coexistence of risk factors was more frequently observed in patient with AO then in the control group. Differences in concentrations of glucosamine and galactosamine between the patients with AO and the control group were not statistically significant in women and only slightly statistically significant in men. CONCLUSIONS: Classical risk factors of CHD differentiate patients with AO from the healthy people. The concentrations of glucosamine and galactosamine in plasma cannot be used to determine the atherosclerosis process.