Neuroleptic Drugs Research Articles

Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study

Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington's Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90%). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472). Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies. Teva Pharmaceutical Industries.

Solid Phase Extraction Purification of Saliva Samples for Antipsychotic Drug Quantitation.

Saliva is far less popular as a diagnostic material than blood. This has resulted in a lack of procedures for the sampling and handling of saliva, e.g., effective ways to purify endogenous compounds from saliva to enable a simultaneous determination of xenobiotics such as neuroleptics. Therefore, the aim of this study was to develop an analytical procedure to purify saliva samples so that it is then possible to simultaneously determine five neuroleptics (aripiprazole, clozapine, olanzapine, quetiapine and risperidone) and the antiepileptic drug carbamazepine, and their respective metabolites (dehydroaripiprazole, N-desmethylclozapine, N-demethylolanzapine, norquetiapine, 9-OH-risperidone and carbamazepine-10,11-epoxide). A study of three types of solid-phase extraction (SPE) columns showed that the purest eluates were obtained using columns containing ion exchange sorbent. The sorbents were first washed with water then with a mixture of water and methanol (1:1), and the adsorbed residue was eluted with a 5% ammonia solution in methanol. Saliva samples for SPE were diluted with 2% formic acid and a mixture of methanol and water (1:1). This procedure was developed to purify a saliva sample spiked with a mixture of neuroleptics and carbamazepine, and their respective metabolites. A chromatographic analysis confirmed the isolation of all compounds, indicating that this procedure can be used in further development and validation for a method designed to monitor the levels of neuroleptic drugs in saliva and to monitor their uptake by patients.

Involvement of vascular endothelial growth factor (VEGF) and mitogen-activated protein kinases (MAPK) in the mechanism of neuroleptic drugs.

Recent evidence suggests that the mitogen activated protein kinase (MAPK)-associated signaling pathway in the frontal cortical areas demonstrates abnormal activity in cases of schizophrenia. Moreover, schizophrenia patients often display alterations in the regional cellular energy metabolism and blood flow of the brain; these are shown to parallel changes in angiogenesis primarily mediated by vascular endothelial growth factor (VEGF). The present study examines the differential effects of time-dependent treatment with haloperidol, olanzapine and amisulpride (20μM) on VEGF and MAPK mRNA expression and VEGF level, using the T98 cell line as an example of nerve cells. For the purposes of comparison, the effect of neuroprotective pituitary adenylate cyclase-activating polypeptide (PACAP) on the expression of VEGF mRNA and secretion were also evaluated in this cell model. RT-PCR analysis revealed that all the tested neuroleptics increased VEGF mRNA expression after 72-h incubation; however, only haloperidol and olanzapine also increased the level of VEGF detected by ELISA, and they demonstrated significantly stronger effects than PACAP. Haloperidol and olanzapine, but not amisulpride, decreased MAPK14 mRNA expression in T98G cells after 72-h incubation. The obtained results suggest that haloperidol and olanzapine can trigger the MAPK and VEGF signaling pathway, which may contribute to their neuroprotective mechanism of action.

Abstract LB-047: Novel anti-psychotic drug for pancreatic cancer treatment

Abstract Pancreatic cancer is one of the most deadly malignancy with a five-year survival rate of 7%. Despite advances in cancer treatment, this disease is still incurable and the treatment outcomes are limited. Few studies have shown that neuroleptic drugs exert better anti-proliferative effects in pancreatic cancer cells when compared to conventional chemotherapeutic agents gemcitabine and oxaliplatin. In the current study, we evaluated the anti-cancer effects of pimavanserin, an anti-psychotic drug used for the treatment of Parkinson's disease psychosis. Pimavanserin significantly suppressed the proliferation of AsPC1, BxPC3, PANC1, MIAPaCa2 and PO2 pancreatic cancer cells with the IC50 between 3 - 9µM at 24, 48 and 72 hours. Pimavanserin treatment induced 2-5 fold apoptosis in pancreatic cancer cells. Notably, no significant cell death was observed in normal human pancreatic ductal epithelial (HPDE-6) cells by pimavanserin treatment. Furthermore, pimavanserin treatment inhibits the expression of key oncogenic proteins and cancer stem cell markers such as pAkt(S473), pSTAT3(Y705), β-catenin, GLI-1, GLI-2, c-Myc, Oct-4, SOX-2, NANOG and CD44. We further evaluated the efficacy of pimavanserin in two different in vivo tumor models. Oral administration of 10mg/kg pimavanserin suppressed 50% of sub-cutaneously implanted BxPC3 tumors in athymic nude mice. In another setting, 10mg/kg pimavanserin by oral gavage inhibited the growth of orthotopically implanted PANC1 pancreatic tumors by 75%. Moreover, chronic administration of pimavanserin did not show any general signs of toxicity and no apparent changes were observed in the behavioral activity of mice. Further mechanistic studies are in progress. Since pimavanserin is already available in the clinic with established safety profile, our results will accelerate its clinical development for treatment of patients with pancreatic cancer. Our study is the first to demonstrate the anti-cancer effects of pimavanserin. Citation Format: Sharavan Ramachandran, Sanjay K. Srivastava. Novel anti-psychotic drug for pancreatic cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-047.

Technical note: can resting state functional MRI assist in routine clinical diagnosis?

Despite some differences in clinical presentation, it is often difficult to differentiate between dementia with Lewy bodies (DLB), clinical Alzheimer’s dementia (AD) and Parkinson’s disease dementia. However, differentiation can be crucial, especially as patients with DLB characteristically have a hypersensitivity to most antiemetic and neuroleptic drugs as they affect the cholinergic and dopaminergic system, potentially leading to life-threatening catatonia, loss of cognitive function and muscle rigidity. The aim of this study is to evaluate if resting state (RS) functional MRI (fMRI) can be used in routine practice on a 1.5 T scanner to differentiate between AD and DLB on an individual basis. We age- and gender-matched a known DLB patient with an AD patient and a human control (HC). Individual independent component analysis was carried out. Region of interest seeds were chosen from the midcingulate and insula regions. Functional connectivity from insula to midcingulate and within the midcingulate network (part of the Salience network) was lower in DLB than AD or HC. RS-fMRI on a 1.5 T scanner, in a routine clinical setting, detected abnormal functional connectivity patterns and allowed differentiation of DLB and AD in a routine clinical setting. This is the first evaluation of RS-fMRI in a routine clinical setting. It shows that incorporating RS-fMRI into the clinical scanning protocol can assist in early diagnosis and likely assist in monitoring the natural history of the disease or disease modifying treatments.

Polimedication: applicability of a computer tool to reduce polypharmacy in nursing homes.

In order to minimize the expenditure of time, our group devised a pilot computer tool (Polimedication) that automatically processes lists of medication providing the corresponding Screening Tool of Older Persons' potentially inappropriate Prescriptions alerts and facilitating standardized reports. The drug lists for 115 residents in Santa Marta Nursing Home (Fundación San Rosendo, Ourense, Spain) were processed. The program detected 10.04 alerts/patient, of which 74.29% were not repeated. After reviewing these alerts, 12.12% of the total (1.30 alerts/patient) were considered relevant. The largest number of alerts (41.48%) involved neuroleptic drugs. Finally, the patient's family physician or psychiatrist accepted the alert and made medication changes in 62.86% of the relevant alerts. The largest number of changes (38.64%) also involved neuroleptic drugs. The mean time spent in the generation and review of the warnings was 6.26 minute/patient. Total changes represented a saving of 32.77 € per resident/year in medication. The application of Polimedication tool detected a high proportion of potentially inappropriate prescriptions in institutionalized elderly patients. The use of the computerized tool achieved significant savings in pharmaceutical expenditure, as well as a reduction in the time taken for medication review.

A successful management with electroconvulsive therapy of neuroleptic malignant syndrome due to amisulpride

Neuroleptic malignant syndrome is a severe complication that mainly occurs based on neuroleptic drug treatment and characterized with some autonomic symptoms, altered mental state, hyperthermia and muscle rigidity. Amisulpride is a unique atypical antipsychotic that selectively blocks D2 and D3 receptors presynaptically in the frontal cortex and atypical antipsychotics are rarely caused neuroleptic malignant syndrome(NMS).This study examine a 20-years old male with the diagnosis of acute psychotic disorder occurred amisulpride-induced NMS and successfully treated with Electroconvulsive Therapy (ECT). We decided to present that case because of the fact that there is only limited number of amisulpride-induced NMS cases reported in the literature.

Functional Changes of Orexinergic Reaction to Psychoactive Substances.

It is becoming increasingly apparent the importance of the central nervous system (CNS) as the major contributor to the regulation of systemic metabolism. Antipsychotic drugs are used often to treat several psychiatric disorders, including schizophrenia and bipolar disorder However, antipsychotic drugs prescription, particularly the second-generation ones (SGAs), such as clozapine and olanzapine, is related to a considerable weight gain which usually leads to obesity. The aim of this paper is to assess the influence of orexin A on sympathetic and hyperthermic reactions to several neuroleptic drugs. Orexin A is a neuropeptide which effects both body temperature and food intake by increasing sympathetic activity. Orexin A-mediated hyperthermia is reduced by haloperidol and is blocked by clozapine and olanzapine. Orexin A-mediated body temperature elevation is increased by risperidone. These hyperthermic effects are delayed by quietapine. In this paper, it is discussed the orexinergic pathway activation by neuroleptic drugs and its influence on human therapeutic strategies. With the aim to determine that neuroleptic drugs mediate body temperature control through to the orexinergic system, we summarized our previously published data. Psychiatric disorders increase the risk of developing metabolic disorders (e.g., weight gain, increased blood pressure, and glucose or lipid levels). Therefore, the choice of antipsychotic drug to be prescribed, based on the relevant risks and benefits of each individual drug, has an essential role in human health prevention.

Medical Emergencies Related to Ethanol and Illicit Drugs at an Annual, Nocturnal, Indoor, Electronic Dance Music Event.

Statistical data on the medical problems encountered during two editions of an indoor electronic dance event with around 30,000 attendants were retrieved from the Belgian Red Cross (Mechelen, Belgium) database. Data on drug use were prospectively collected from the patient (or a bystander), the clinical presentation, and/or toxicological screening. In the on-site medical station, 487 patients were treated (265 in 2013 and 222 in 2014). The most frequent reasons were trauma (n=171), headache (n=36), gastro-intestinal problems (n=44), and intoxication (n=160). Sixty-nine patients were transferred to a hospital, including 53 with severe drug-related symptoms. Analysis of blood samples from 106 intoxicated patients detected ethanol in 91.5%, 3,4-methylenedioxymethamphetamine (MDMA) in 34.0%, cannabis in 30.2%, cocaine in 7.5%, amphetamine in 2.8%, and gamma-hydroxybutyric acid (GHB) in 0.9% of patients (alone or in combination). In only six of the MDMA-positive cases, MDMA was the sole substance found. In 2014, the neuroleptic drug clozapine was found in three cases and ketamine in one. Additional analyses for NPS were performed in 20 cases. Only in one agitated patient, the psychedelic phenethylamines 25B-NBOMe and 25C-NBOMe were found. At this particular event, recreational drug abuse necessitated on-site medical treatment in one out of 350 attendants and a hospital transfer in one out of 1,000. Ethanol remains the most frequently abused (legal) drug, yet classical illicit recreational drugs are also frequently (co-) ingested. The most worrying observation was high-risk poly-drug use, especially among MDMA users. Regarding NPS, the number of cases was low and the clinical presentations were rather mild. It should be stressed that these observations only apply to this particular event and cannot be generalized to other EDM events. Calle P , Sundahl N , Maudens K , Wille SMR , Van Sassenbroeck D , De Graeve K , Gogaert S , De Paepe P , Devriese D , Arno G , Blanckaert P . Medical emergencies related to ethanol and illicit drugs at an annual, nocturnal, indoor, electronic dance music event. Prehosp Disaster Med. 2018;33(1):71-76.

A Review of Clinical and Economic Evaluations Applied to Psychotropic Therapies Used in the Treatment of Schizophrenia in Argentina.

Schizophrenia is considered a serious mental disorder that affects over 21 million people worldwide, and is associated with disability that frequently affects the patient’s educational and working performance. In Argentina, two of the most widely used antipsychotics in the treatment of this disorder are haloperidol and risperidone. Both are provided free to patients without health coverage in public healthcare facilities. In this paper we seek to review the clinical and economic benefits of prescribing psychotropic therapies based on haloperidol (a first-generation antipsychotic that is part of the butyrophenone group of drugs) versus risperidone [an atypical or second-generation antipsychotic (neuroleptic) drug] in adult patients who have been diagnosed with schizophrenia. To achieve this objective, an exhaustive search of relevant articles published between 2006 and April 2017 was conducted. This literature search showed that intermittent treatment usually fails to prevent relapses due to irregular protection, therefore continuous treatment is more effective. Although the injectable formats of both drugs [haloperidol depot and long-acting injectable risperidone (LAIR)] have not proven to have significant differences with regard to clinical effectiveness vis-à-vis the tablet formats, they showed a lower cost-effectiveness ratio by reducing patients’ relapses. Moreover, LAIR exhibits superior cost effectiveness compared with haloperidol depot. Haloperidol is less expensive than risperidone but is less cost effective; in comparison with haloperidol, treatment with risperidone produces (1) an improvement in quality-adjusted life-years, and (2) a significant reduction in negative symptoms. In most cases, antipsychotic treatments are effective in controlling the positive and negative symptoms associated with schizophrenia, allowing patients to live in their communities without any impairments. However, it is extremely important to combine pharmacological treatment with other measures that constitute psychosocial therapy.

Temporomandibular joint dislocation in an epileptic and mentally retarded patient: a case report.

Temporomandibular joint (TMJ) dislocation is defined as an excessive forward movement of the condyle beyond the articular eminence with complete separation of articular surfaces and fixation in that position.' Theories regarding the pathogenesis of TMJ dislocation propose laxity of TMJ ligaments or capsule, excessive activity of the lateral pterygoid muscle (LPM)and erosion of the eminence'. TMJ dislocation can occur in an anterior, posterior, lateral and superior direction'. Clinical presentation of dislocated TMJ includes inability to close the mouth, deviation of the mandible away from the affected side in unilateral cases, hollowing in front of the tragus, spasm of muscles of mastication and severe pain of the TMt Radiographs show an empty condylar fossa with the condylar head located anterior to the articular eminence. Anterior TMJ dislocation usually follows excessive mouth opening during yawning, laughing, eclamptic fit and motor vehicle accident (MVA)'. Iatrogenic causes of TMJ dislocation are excessive mouth opening during dental treatment, intubation, and otorhinolaryngological procedures Some drugs are associated with TMJ dislocation, these include antiemetics such as metoclopramide and compazine which produce extrapyramidal effects' and neuroleptic drugs. Systemic connective diseases like Ehlers-Danlos and Marfan syndromes have also been implicated in TMJ dislocations The purpose of this article is to report management challenges of an epileptic and mentally retarded patient with recurrent TMJ dislocation.

Advanced breast cancer patients: role of neuroleptic drugs

Advanced breast cancer patients: role of neuroleptic drugs

P.3.d.002 - Pharmacological management of antipsychotic-induced obesity – a systematic literature review

Neuropeptides play an important role in various neural pathways, being able to control a wide spectrum of physiological responses. Neuropeptide Y (NPY) and proopiomelanocortin (POMC) functions are quite well studied, however little is known about their action at the level of limbic structures. The present work was focused on the expression of the aforementioned peptides in this brain structure of rats treated with olanzapine, a second generation neuroleptic drug. The detailed purpose of this experiment was the evaluation of potential relationships between chronic olanzapine administration and NPY and POMC mRNA expression in the amygdala and hippocampal formation.The studies were carried out on adult, male Sprague-Dawley rats that were divided into 2 groups: control and experimental animals treated with olanzapine (28 day-long intraperitoneal injection). All individuals were sacrificed under anaesthesia, then the amygdaloid complexes and hippocampi were excised. Total mRNA was isolated from homogenized samples of both structures and the RT-PCR method was used for estimation of NPY and POMC gene relative expression.Prolonged olanzapine administration is reflected in qualitatively different changes in expression of NPY and POMC mRNA in the rat amygdala and hippocampus. Interestingly enough, olanzapine did not affect NPY expression, but significantly increased the POMC level in both examined regions.Olanzapine can affect amygdalar and hippocampal neuronal populations by the modulation of neuropeptide activity. Importantly, it may suggest the existence of an alternative mode of its action. Undoubtedly this hypothetic regulatory mechanism requires further pharmacological and neurostructural study.

The Effect of Chronic Treatment with Lurasidone on Rat Liver Cytochrome P450 Expression and Activity in the Chronic Mild Stress Model of Depression.

Recent studies indicated an important role of the monoaminergic nervous systems (dopaminergic, noradrenergic, and serotonergic systems) and stress in the regulation of cytochrome P450 (CYP) expression and activity in the liver. The aim of our present research was to determine the effect of the novel atypical neuroleptic drug with antidepressant properties lurasidone, on the expression (mRNA and protein level) and activity of liver CYP isoforms involved in the metabolism of drugs and endogenous steroids, in the chronic mild stress (CMS) model of depression. Male Wistar rats were subjected to CMS for 7 weeks. Lurasidone (3 mg/kg per os per day) was administered to nonstressed or stressed animals for 5 weeks (weeks 3-7 of CMS). It has been found that 1) CMS moderately affects CYP (CYP2B, CYP2C11, and CYP3A), and its effects are different from those observed after other kinds of psychologic stress, such as repeated restraint stress or early-life maternal deprivation; 2) chronic lurasidone influences the expression and/or activity of CYP2B, CYP2C11, and CYP3A isoforms; and 3) CMS modifies the action of lurasidone on CYP expression and function, leading to different effects of the neuroleptic in nonstressed and stressed rats. Based on the obtained results, it can be suggested that the metabolism of endogenous substrates (e.g., steroids) and drugs, catalyzed by the isoforms CYP2B, CYP2C11, or CYP3A, may proceed at a different rate in the two groups of animals (nonstressed and stressed) in the rat CMS model.

Effects of Pimozide Derivatives on pSTAT5 in K562 Cells.

STAT5 is a transcription factor, a member of the STAT family of signaling proteins. STAT5 is involved in many types of cancer, including chronic myelogenous leukemia (CML), in which this protein is found constitutively activated as a consequence of BCR-ABL expression. The neuroleptic drug pimozide was recently reported to act as an inhibitor of STAT5 phosphorylation and is capable of inducing apoptosis in CML cells in vitro. Our research group has synthesized simple derivatives of pimozide with cytotoxic activity and that are able to decrease the levels of phosphorylated STAT5. In this work we continued the search for novel STAT5 inhibitors, synthesizing compounds in which the benzoimidazolinone ring of pimozide is either maintained or modified, in order to obtain further structure-activity relationship information for this class of STAT5 inhibitors. Two compounds of the series showed potent cytotoxic activity against BCR-ABL-positive and pSTAT5-overexpressing K562 cells and were able to markedly decrease the levels of phosphorylated STAT5.

33 Tolerability of neuroleptics for tourette syndrome

<h3>Objective</h3> Pharmacological treatments of Tourette Syndrome (TS) are variable in their efficacy and tolerability between patients. Most studies examine a single drug with a focus on effective treatment. We aimed to identify the frequency of treatment limiting adverse effects seen in TS patients prescribed one of the most commonly used first line groups of drugs, neuroleptics. <h3>Method</h3> 185 sets of clinical notes from a dedicated Tic Disorder clinic were retrospectively reviewed. These represented patients with surnames starting A-G over a 10 year period and 107 were over 18 years old. Neuroleptic prescriptions and the outcome in terms of tolerability at the next clinical review was recorded, but mentions of historical treatment before reaching our clinic were not included. <h3>Results</h3> 111/185 members of the cohort were not prescribed neuroleptics, or were not at the time of study monitored for at least one review visit. The most used drug was Aripiprazole in 66 patients – 75% of all neuroleptic drugs prescribed. 18% were stopped due to side effects and 12% were reduced in dose due to side effects; so, 30% of Aripiprazole prescriptions were associated with limiting adverse side effects. Tiredness was most common (n=8), followed by weight gain (n=5) and sedation (n=4). 15 prescriptions of Aripiprazole were associated with no reported side effects. 22 patients were prescribed other neuroleptics and further information will be presented. <h3>Conclusion</h3> The majority of patients do not report adverse effects and continue with their Aripiprazole prescription. Around 18% discontinued the drug due to adverse effects, in line with previous data. The study was limited by short follow-up times as other patients may subsequently experience treatment-limiting side effects after successful early review. In recent years Aripiprazole tended to be the first line neuroleptic used, so data on other less used alternatives may be biassed by being prescribed after one agent had already failed due to adverse effects or lack of efficacy.

Confirmation of metabolites of the neuroleptic drug prothipendyl using human liver microsomes, specific CYP enzymes and authentic forensic samples—Benefit for routine drug testing

Metabolism of the tricyclic azaphenothiazine neuroleptic drug prothipendyl was investigated with in vitro studies using human liver microsomes but also specific isoforms of cytochrome P450 (CYP) enzymes. Identification and analysis of metabolites was done by liquid chromatography (LC) coupled with quadrupole time of flight mass spectrometry (LC-QTOF-MS) as well as triple quadrupole mass spectrometry (LC-QQQ-MS).Results of the herein presented study revealed the proof of various demethylated and oxidized metabolites (-CH2, -C2H4, four derivatives of prothipendyl +O and three derivatives of prothipendyl -CH2+O). Metabolic reactions of prothipendyl were mainly catalyzed by CYP enzymes CYP1A2, CYP2D6, CYP2C19 and CYP3A4. N-demethyl-prothipendyl was predominantly formed by isoforms CYP2C19 and CYP1A2, while particularly the CYP isoenzyme 3A4 was responsible for the formation of prothipendyl sulfoxide.To confirm the formation of previously identified metabolites in vivo, cardiac blood samples that were tested positive for prothipendyl during routine drug testing and serum and urine samples, collected after a voluntary intake of prothipendyl, were analyzed by LC-QQQ-MS. All metabolites of prothipendyl were proven in these authentic specimens. Neither in serum samples nor in urine samples, a prolonged detectability of metabolites in comparison to prothipendyl could be demonstrated.

DEMENTIA WITH LEWY BODY (DLB) SYMPTOMS HIDDEN WITHIN THE DIAGNOSIS ‘DEMENTIA NOT OTHERWISE SPECIFIED’: A CROSS-SECTIONAL STUDY IN 40 SWEDISH NURSING HOMES

Background: Dementia with Lewy Body (DLB) is a neurocognitive disorder with core features, such as Parkinsonism, visual hallucinations, and fluctuating cognition/ excessive daytime sleepiness, and supportive features, such as rapid eye movement sleep behaviour disorder. DLB is often misdiagnosed and unrecognized in elderly individuals. A diagnosis of DLB is important because of the risk of hypersensitivity for neuroleptic drugs. Moreover, appropriate treatment of symptoms can improve quality of life considerably for both the individual with DLB and their caregivers. Primary care uses often diagnose Dementia Not Otherwise Specified (NOS) that may lead to an increased risk of wrong medical treatment and lack of proper elderly care. Especially if the elderly had a misdiagnosed or undefined DLB symptomatology. We hypothesized that potential DLB symptoms were hidden within the Dementia NOS diagnosis. Methods: A questionnaire designed to cover the main DLB symptoms (according to DLB consensus criteria from 2005) was distributed to all 40 primary care nursing homes (NHs) and geographically entirely covering the third largest Swedish city. Nursing staff completed the questionnaires after receiving specifically designed teaching. Results: The participants were elderly (n=650) from all NHs (n=40) where 94% (n=610) were included of which (n=595) had available medical records. The mean age was 86.0 ± 7.5 years; 75% (n=467) were women. The prevalence of elderly with Dementia NOS was 20% (n=121), AD 19% (n=115), AD-Mix 16% (n=97), VaD 14% (n=85), DLB/PDD 5% (n=22) and in 26% (n=155) no formal dementia diagnosis was found. Finally, according to the questionnaire, 16% of all the participants had two or more main symptoms of DLB (2-4 DLB smp.) According to the questionnaire, the elderly with the Dementia NOS diagnosis 85% had 0-1 DLB smp. and 15% had 2-4 DLB smp. Conclusion: We conclude that within the dementia NOS diagnose elderly with hidden DLB symptoms constitute 15% leading to risk of potentially harmful medication. Recognizing signs of dementia with Lewy bodies could reduce the number of individuals with Dementia NOS diagnosis and give opportunity to more suitable and less potentially harmful medication in nursing homes. (Less)

SAFETY AND EFFICIENCY OF ANTI-PARKINSON DRUGS FOR DLB/PDD PATIENTS

One of the characteristic features of DLB (Dementia with Lewy Body) is high sensitivity to medicine, including not only neuroleptic drugs but also anti-parkinson drugs. Once hallucinations or systematized delusions were induced, it is too difficult to control psychiatric disorders as well as parkinsonism. The aim of this study is to decide the best anti-parkinson drug(s) for the treatment of parkinsonism with DLB and PDD (Parkinson’s disease with Dementia) patients. 28 patients diagnosed with DLB and 20 diagnosed with PDD were examined. Their histories of prescription medication and those of side effects were obtained retrospectively from medical records. [Results] Among 48 patients, 9 cases were not prescribed any anti-parkison drugs at all. Another 21 cases had some side effects, such as temporary hallucinations, delusions or nausea. Antiparkison medications causing frequent side effects included trihexyphenidyl (100%), amantazine (67%), istradefylline (63%), selegiline (50%) and dopamine agonists (33%). On the other hand, entacapone (10%), zonisamide (11%) and levodopa with carbidopa or benserazide (13%) seemed to be relatively safer for DLB/PDD patients. As to dopamine agonist, rotigotine (25%) showed lower rate of side effects than pramipexole (45%) and ropinirole (40%). In conclusion, for the treatment of parkinsonism in cases of DLB/PDD, levodopa/carbidopa or benserazide is the first choice, however, if more anti-parkinson therapy is necessary, the second candidate is zonisamide and/or entacapone from the viewpoint of safety.

Sulpiride, Amisulpride, Thioridazine, and Olanzapine: Interaction with Model Membranes. Thermodynamic and Structural Aspects.

Neuroleptic drugs are widely applied in effective treatment of schizophrenia and related disorders. The lipophilic character of neuroleptics means that they tend to accumulate in the lipid membranes, impacting their functioning and processing. In this paper, the effect of four drugs, namely, thioridazine, olanzapine, sulpiride, and amisulpride, on neutral and negatively charged lipid bilayers was examined. The interaction of neuroleptics with lipids and the subsequent changes in the membrane physical properties was assessed using several complementary biophysical approaches (isothermal titration calorimetry, electron paramagnetic resonance spectroscopy, dynamic light scattering, and ζ potential measurements). We have determined the thermodynamic parameters, that is, the enthalpy of interaction and the binding constant, to describe the interactions of the investigated drugs with model membranes. Unlike thioridazine and olanzapine, which bind to both neutral and negatively charged membranes, amisulpride interacts with only the negatively charged one, while sulpiride does not bind to any of them. The mechanism of olanzapine and thioridazine insertion into the bilayer membrane cannot be described merely by a simple molecule partition between two different phases (the aqueous and the lipid phase). We have estimated the number of protons transferred in the course of drug binding to determine which of its forms, ionized or neutral, binds more strongly to the membrane. Finally, electron paramagnetic resonance results indicated that the drugs are localized near the water-membrane interface of the bilayer and presence of a negative charge promotes their burying deeper into the membrane.