Insomnia, the experience of poor quality or quantity of sleep, is a very common complaint. In the community estimates for the current prevalence of insomnia range from 15 to 28%. Pharmacological treatment of insomia is faster and more effective than other treatments, including psychotherapy, hypnosis, and so on. In pharmacological treatment, benzodiazepines (BZDs) and non-benzodiazepines, including zolpidem, are very common prescribing hypnotic usages because of more effectiveness and safer side-effect profiles. Our retrospective, current observational study is a chart review of 3,152 psychiatric outpatients, attempted to review adverse effects, specifically somnambulism and antegrade amnesia after these medications, to see whether or not, this is an infrequent occurrence in Taiwan population. Of a total 406 long-/intermitted-half-life BZD hypnotics users, 0.25% (1 of 406) reported incidence of somnambulism and anterograde amnesia. However, 5.1% (13 of 255) reported incidence of zolpidem-induced somnambulism and anterograde amnesia. It serves as a reminder for clinicians to inquire of spouses (bed parters) of the patients about any unusual behavior of parasomnia activities when prescribing zolpidem, specifically in Taiwan population.

Catatonia is a neuropsychiatric condition characterized by physical presentations ranging from profound immobility to excessive motor activity. In the past, catatonia was considered a variant of schizophrenia. However, newer data suggests catatonia is a clinical expression of many different medical or psychiatric components. A prompt diagnostic evaluation should identify any underlying diseases with consideration of somatic pathologies, especially those affecting central nervous system function. The recognition of catatonia among providers is relatively poor. It is often seen as a historical diagnosis. Because of this, catatonia is often undiagnosed. If patients in catatonic states are not diagnosed, their condition is likely to progress with a risk of increased morbidity and potentially fatal outcome. Lorazepam or electroconvulsive therapy (ECT) are considered the standard of care for treatment of catatonia. Zolpidem has been used successfully as a rapid test for patients suspected to be catatonic.This case report explores zolpidem as a long-term treatment option when standard therapies are not tolerated or ineffective. In order to recognize catatonia, apart from thorough and repeated observation, a clinical examination is needed. The Bush-Francis Catatonia Rating Scale is a quantifiable examination designed to screen and diagnose the possibility of catatonia. We investigated Zolpidem’s impact on a patient’s Bush-Francis Catatonia Rating Scale score. Scores were collected weekly for two months. There were five different resident physicians who conducted these examinations. Results of this work identified a reduction in Bush-Francis Catatonia ratings in seven out of the eight weeks of this study, suggesting that there may be a link between Zolpidem use and a reduction in catatonic symptoms. Limitations to this study included the subjective nature of the rating scale, along with the potential for variability in assessment standards, stemming from the fact that multiple examiners were used to conduct ratings. Because catatonia is a medical emergency, it is of utmost importance to gather a detailed history and conduct a rigorous medical workup to help confirm the diagnosis. While Lorazepam and ECT remain the standard of care, this study demonstrates that there may be a potential benefit to the use of Zolpidem in catatonia.

Made available in DSpace on 2015-07-22T20:49:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-11-24 / O zolpidem é um derivado imidazopiridínico com crescente utilização terapêutica que se liga ao sítio BZ1 dos receptores GABAA. Essa seletividade deveria conferir ao zolpidem propriedades predominantemente hipnóticas e ausência relativa dos efeitos colaterais que são associados aos benzodiazepínicos clássicos, como por exemplo, efeitos anticonvulsivantes e relaxantes musculares e, de importância, a amnésia. Entretanto, investigações clínicas e em modelos animais têm revelado efeitos amnésticos após a administração aguda de zolpidem. Nesse contexto, considerando a crescente utilização do zolpidem no tratamento da insônia, faz-se necessária a caracterização dos efeitos cognitivos induzidos por essa droga bem como seus efeitos na atividade motora e na emocionalidade. Assim, nossos resultados sugerem que a administração aguda pré-treino de zolpidem promoveu prejuízos de aprendizado na dose de 10 mg/Kg, mas não nas doses de 2 e 5 mg/Kg, e promoveu uma diminuição da atividade exploratória de maneira dependente de dose, sem, no entanto, modificar a ansiedade. No que diz respeito à memória, observamos déficits de retenção nas doses de 5 e 10 mg/Kg. Quando administrado imediatamente após o treino, todos os animais tiveram a memória preservada. Ainda, a administração pré-teste de todas as doses de zolpidem não modificou o desempenho dos animais, demonstrando a ausência de efeitos sobre a evocação. Paralelamente, nossos resultados não sugerem a participação do fenômeno de dependência de estado, uma vez que a administração aguda de zolpidem anteriormente ao treino e ao teste não foi capaz de reverter o prejuízo de memória induzido pela administração pré-treino dessa droga. Com relação à memória não-associativa, observamos que na dose de 10 mg/Kg o zolpidem promove déficits de habituação no modelo de campo aberto, além de diminuir a atividade exploratória, como visto anteriormente. Dessa maneira, demonstramos que apesar de sua seletividade, o zolpidem pode induzir déficits de memória associativa (e também não-associativa) quando administrado anteriormente ao treino da tarefa, interferindo talvez, no início do processo de consolidação. / Zolpidem is an imidazopyridine agent with crescent therapeutic employment which binds selectively to the BZ1 site into the GABAA receptors. This selectivity seems to confer zolpidem its mainly hypnotic properties with relative absence of side effects which are associated to classical benzodiazepines, for example anticonvulsant and miorelexant effects and, importantly, amnesia. Although, clinical studies and in animal models have demonstrated amnestic effects after the acute administration of zolpidem. In this context, considering its crescent employment in the insomnia treatment, it is necessary to characterize the cognitive effects induced by this drug and also its effects on exploratory activity and emotionality. Thus, our results suggest that the pre-training acute administration of zolpidem promoted learning impairments on the dose of 10 mg/Kg, but not on the doses of 2 and 5 mg/Kg, and promoted a decrement on exploratory activity in a dose-dependent manner, but did not modified anxiety. In respect with memory, we observed retention deficits on the doses of 5 and 10 mg/Kg. When administered immediately after training, all animals had their memory preserved. Still, the pre-test administration of all doses of zolpidem did not modify animal’s performance, showing the lack of effects on retrieval. In parallel, our result did not suggest the influence of state-dependency phenomenon once the acute administration of zolpidem before training and testing did not reverse the memory impairment induced by pre-training administration of this drug. In relation to non-associative memory, we observed that 10 mg/Kg zolpidem promoted habituation deficits on the open-field model. Furthermore, it promoted a decrement on exploratory activity, corroborating previous results. In this way, we demonstrated that besides its selectivity, zolpidem can induce associative memory deficits (as non-associative) when administered before the training of the task interfering, maybe, on the consolidation process. / TEDE / BV UNIFESP: Teses e dissertações

Tesis para Optar al Grado Académico de Magíster en Bioquímica, Área de Especialización: Toxicología y Diagnóstico Molecular / Memoria para Optar al Título de Bioquímica / El ser humano está constantemente expuesto a agentes externos (xenobióticos), entre los que se incluyen los fármacos. La mayoría de estos xenobióticos son lipofílicos siendo absorbidos por la mucosa gastrointestinal hacia la circulación sistémica. Para facilitar su excreción existen enzimas de biotransformación, tales como las monooxigenasas o citocromo P450 (CYP), las cuales se encuentran principalmente en el hígado y transforman sustancias lipofílicas en compuestos hidrofílicos modificando la velocidad de excreción, la vida media y otras propiedades fármaco/tóxicocinéticos. La variabilidad interindividual en el metabolismo y respuesta a fármacos es extensa debido a las características genéticas individuales y las interacciones con otros xenobióticos. Este tema es abordado por la farmacogenética, una disciplina que analiza la información genética del paciente para diseñar una terapia farmacológica más apropiada y por consiguiente, la información previa de esto puede ser beneficiosa, en especial en aquellos fármacos con un índice terapéutico estrecho o una concentración plasmática mínima. Ello debido a que es bien sabido que la mayoría de las enzimas de biotransformación son polimórficas, causando ya sea la supresión, disminución o aumento del metabolismo de fármacos. Por lo tanto, es necesario conocer su variación en un individuo para ajustar una terapia farmacológica individualizada. Una de las enzimas relevantes en la respuesta farmacológica, responsable del metabolismo de gran cantidad de fármacos y que corresponde casi al 30% de las enzimas P450 hepáticas es CYP3A4. Se han descrito numerosos polimorfismos en el gen que codifica para esta enzima, siendo CYP3A4*1B uno de los más estudiados. Al respecto, estudios in vitro han mostrado que esta variante exhibe una actividad enzimática dos veces menor que el genotipo común o wild type CYP3A4 wt/wt, sin embargo, in vivo no se ha logrado demostrar que esta variante esté asociada a una disminución de la actividad enzimática. El medicamento hipnosedativo Zolpidem utilizado para iniciar o mantener el sueño es biotransformado principalmente por CYP3A4, por lo que esta enzima puede tener un papel muy relevante en la respuesta farmacoterapéutica. A pesar de que se han realizado estudios in vitro que han demostrado su biotransformación por CYP3A4 (61%), CYP2C9 (22%) y CYP1A2 (14%), aún no se demuestra que la presencia del polimorfismo de CYP3A4 *1B altere los parámetros farmacocinéticos en humanos, ya sea sometidos a monodosis o a un tratamiento con Zolpidem. De acuerdo a estos antecedentes, el objetivo del presente trabajo de tesis persiguió determinar la frecuencia del polimorfismo CYP3A4 *1B en la población chilena sana, y asociar el polimorfismo a cambios en los parámetros farmacocinéticos de Zolpidem en un grupo de voluntarios sanos sometidos a una monodosis de Zolpidem. La detección de los diferentes genotipos se realizó a través de PCR-RFLP convencional y los parámetros farmacocinéticos se obtuvieron mediante análisis por cromatografía líquida de alta resolución (HPLC). Los resultados obtenidos mostraron una frecuencia genotípica de un 0,889 para el genotipo silvestre (wt/wt), 0,111 para los heterocigotos (wt/*1B) y no se encontraron individuos homocigotos mutados (*1B/*1B) en 253 chilenos sanos. La frecuencia alélica fue de un 0,945 para el alelo silvestre (wt) y un 0,055 para el alelo mutado (*1B). El análisis estadístico para establecer la relación entre el genotipo y los parámetros farmacocinéticos de 32 personas estudiadas (28 para wt/wt y 4 para wt/*1B) no mostró una asociación estadísticamente significativa, por lo que sería necesario disponer de un mayor número de individuos tratados con el fármaco de modo de establecer la presencia de metabolizadores rápidos o lentos de Zolpidem o en su defecto realizar un estudio farmacocinético en un grupo de individuos previamente identificados como portadores del alelo mutado. Sin perjuicio de lo anterior, es necesario destacar que el objeto último de la farmacogenética es establecer respuestas individuales, por lo que el hallazgo de 4 individuos con genotipo mutado y el análisis de sus niveles plasmáticos de Zolpidem podrían permitir disponer de una herramienta útil para el ajuste de la dosis de este medicamento. / Human beings are constantly exposed to external agents (xenobiotics), including drugs. Most of xenobiotics are lipophilic and therefore they are absorbed by gastrointestinal mucous towards the systemic circulation. To facilitate their excretion biotransformation enzymes, such as monooxygenases or cytochrome P450 (CYP), found mainly in the liver, change lipophilic substances to hydrophilic compounds by modifying their excretion rate, half-life, and other pharmacokinetics or toxicokinetics properties. The interindividual variability in metabolism and drug responses is huge because of individual genetics characteristic and interactions with other xenobiotics. This topic is approached by pharmacogenetics, an area that analyzes the genetic makeup of patients a suitable pharmacological therapy design and therefore. The knowledge derived from this research can be beneficial, especially for those drugs with a tight therapeutic index or minimum plasmatic concentration. Since it is well-known that most biotransformation enzymes are polymorphic, causing suppression, decrease or increase of drug metabolism, it is necessary to know individual variation to fit an individualized pharmacology therapy. One of the relevant enzymes responsible for the metabolization of many drugs and part of hepatic P450 enzymes is CYP3A4. This enzyme presents several polymorphisms, being CYP3A4*1B one of the most studied. In vitro studies have shown that this variant shows only half of the enzymatic activity of the common genotype (CYP3A4 wild type). It has not been shown in vivo that this variant is associated to an enzymatic activity reduction. The hypnosedative drug Zolpidem used to induce or maintain sleep is mainly biotransformed by CYP3A4, therefore this enzyme may have a relevant role in the pharmacotherapeutic response. In spite of in vitro studies have demonstrated its biotransformation by CYP3A4 (61%), CYP2C9 (22%) and CYP1A2 (14%), it still has not been shown that the presence of the CYP3A4*1B polymorphism modifies zolpidem pharmacokinetic parameters in humans, whether they are administered as a monodose or a treatment sustained. The goal of this thesis was to determine CYP3A4*1B polymorphism frequency in a healthy Chilean population and in a group of healthy volunteers under a Zolpidem monodose treatment, and to relate the genotypes frequencies to changes in Zolpidem pharmacokinetic parameters. Detection of correlated genotypes were realized through conventional PCR-RFLP and the pharmacokinetic parameters were measured through high performance liquid chromatography (HPLC) analysis. The results showed a genotypic frequency of 0,889 for the wild type genotype (wt/wt) and 0,111 for heterozygous (wt/*1B). We did not find homozygote individuals for the (*1B/*1B) genotype in 253 healthy Chileans. The allelic frequency was 0,945 for the wild type allele (wt) and 0,055 for mutated allele (*1B). The statistic analysis to establish the relation among genotype and pharmacokinetic parameters of 32 individuals (28 wt/wt and 4 wt/*1B) did not show a significant statistically association. It will be necessary to analyze a higher number of subjects treated with the drug to establish rapid or poor Zolpidem metabolizers. Alternatively a pharmacokinetic study can be restored in a group previously identified as carriers of mutated allele. It is important to stand out that the final purpose of pharmacogenetics is the establishment of individual answers, therefore, the finding of wt/*1B genotype subjects together with their plasma levels of Zolpidem could permit us to have an useful tool to fit the drug posology.

The prevalence of drugged driving has increased in the United States, and some prescription medications (e.g., zolpidem) cause impairment after the predicted duration of therapeutic action has elapsed. The aim of this study is to determine if bedtime administration of alprazolam similarly impacts driving performance the following day. Volunteers were 14 healthy adults (6 males) who completed a double-blind, double-dummy within-subjects design study examining the effects of alprazolam (0.5, 1, & 2mg), zolpidem (10mg), and placebo administered at bedtime on driving performance the following day. The positive control condition was alprazolam (1mg) administered on the test morning. Driving simulator measures, cognitive and psychomotor tasks, and questionnaires querying drug effects were collected the afternoon before drug administration and for 5.5 hours the next day and analyzed using symmetry and mixed-model approaches. The positive control was robustly impairing. Driving impairment equivalent to that seen with alcohol at the legal limit was observed up to 12.5hr after bedtime alprazolam 2mg and for 8.5hr after bedtime zolpidem 10mg. Volunteers were not fully aware of their own level of impairment. These results suggest that alprazolam used before bed may pose an as yet unrecognized public safety risk in the form of next-day drugged-driving.

Reproduction de : Thèse d'exercice : Médecine. Médecine générale : Nantes : 2008. / Bibliogr.

No description available.

This project represents one of the foundation steps to a collaboration between the Department of Human Physiology, University of Pretoria and the Nuclear Medicine Department at Steve Biko Academic hospital. Following the initial discovery of the surprising effect zolpidem has on patients in persistent vegetative states in 1999 by Dr H.W. Nel - namely that zolpidem administration results in a significant qualitative increase in brain function, to the extent that patients were able to once again communicate and respond appropriately to their surroundings - much data has been collected by both Dr Nel as well as the Nuclear Medicine Department of Steve Biko Hospital. Over the course of twelve years SPECT scans have been carried out on patients of various pathologies both before and after a course of zolpidem. To this day, both assessment and follow up of these and new patients is still being done by the Nuclear Medicine Department and Dr Nel. As this vast collection of data grows it has become increasingly daunting for a single research team to consolidate all this information into a usable form and an outside team has been deemed necessary to facilitate this process. The primary goal of this study was to quantify the neurological perfusion changes following zolpidem administration within responder patients. This was achieved through reprocessing and semi-quantification of the existing SPECT scan records held by the Pretoria Academic Hospital. Within the group of responder patients (n = 29), 22 patients (~76%) presented a significant increase in perfusion within at least one lesion with a range of 4.5 - 46.1% (mean = 11.9%). In opposition to this finding non-responsive lesion perfusion decreased with a significant mean change of -14.5%. For both sets the p-value was determined to be <0.01. Of all lesions measured (n = 85) 32% displayed increased perfusion after zolpidem administration, whereas 30.6% presented with a perfusion decrease. It was determined that only one lesion is required to respond to zolpidem in a positive manner to facilitate positive functional improvements with a given patient. In a small minority of patients post-zolpidem functional improvements seems to be connected to wide-spread cortical changes as opposed to singular lesional improvements. This study provides further evidence of zolpidem’s paradoxical action in a subset of brain damaged individuals. Unique quantification of results allows for additional insight and provides further understanding the physiological changes associated with zolpidem administration. / Dissertation (MSc)--University of Pretoria, 2014. / tm2015 / Physiology / MSc / Unrestricted

Η ΒΥΠ διαθέτει αντίτυπο της διατριβής σε έντυπη μορφή στο βιβλιοστάσιο διδακτορικών διατριβών που βρίσκεται στο ισόγειο του κτιρίου της. / Ο ιππόκαμπος στον αρουραίο είναι μια δομή σε C-σχήμα που εκτείνεται από τον διαφραγματικό πυρήνα προσθιοραχιαία έως τον κροταφικό λοβό οπισθιοκοιλιακά. Παρόλο που από παλιά θεωρείτο ως ομοιογενής δομή, έχουν παρατηρηθεί πολλές διαφορές σε όλα τα επίπεδα οργάνωσης μεταξύ του διαφραγματικού και του κροταφικού ιππόκαμπου. Οι βενζοδιαζεπίνες δρουν στις θέσεις δέσμευσης των βενζοδιαζεπινών, οι οποίες είναι αλλοστερικά συνδεδεμένες με το σύμπλοκο του GABAA, όπου ενισχύουν την δράση του GABA στους GABAA υποδοχείς, αυξάνοντας τη συχνότητα ανοίγματος του διαύλου των ιόντων χλωρίου (Cl-) και έχοντας μικρή μόνο επίδραση στο χρόνο ανοίγματος ή στην αγωγιμότητα του διαύλου. Προηγούμενη μελέτη υποδεικνύει ότι η έκφραση των α1-, β2- και γ2-υπομονάδων ήταν μικρότερη, ενώ αντίθετα η έκφραση των α2-, α5- και β1-υπομονάδων ήταν μεγαλύτερη στον κροταφικό ιπποκάμπο σε σύγκριση με τον διαφραγματικό ιππόκαμπο. Σύμφωνα με προηγούμενες μελέτες που αφορούν την συνέκφραση των υπομονάδων στο σύμπλοκο του GABAA υποδοχέα τα αποτελέσματα μας υποδηλώνουν ότι ο α1β2-υποτύπος του GABAA υποδοχέα επικρατεί στον διαφραγματικό ιππόκαμπο (ΔΙ), ενώ ο α2β1-υπότυπος κυριαρχεί στον κροταφικό ιππόκαμπο (ΚΙ). Επιπλέον, φαρμακολογικές μελέτες έχουν δείξει ότι η καταπραϋντική δράση της diazepam πραγματοποιείται μέσω των GABAA υποδοχέων, που περιέχουν την α1-υπομονάδα, ενώ η αγχολυτική δράση της πραγματοποιείται μέσω των υποδοχέων που φέρουν την α2-υπομονάδα. Επομένως, η μελέτη των φαρμακολογικών ιδιοτήτων των υποτύπων του GABAΑ υποδοχέα δίνει την δυνατότητα στο να σχεδιαστούν ειδικά φάρμακα τα οποία θα βελτιώνουν το κλινικό προφίλ ασθενειών, όπως το άγχος, η αϋπνία ή η επιληψία, δρώντας σε εξειδικευμένους υποτύπους του GABAΑ υποδοχέα. Ο στόχος της συγκεκριμένης εργασίας ήταν να μελετηθούν οι φαρμακολογικές ιδιότητες των υποτύπων του συμπλόκου του GABAA υποδοχέα/βενζοδιαζεπινών στον διαφραγματικό σε σύγκριση με τον κροταφικό ιππόκαμπο επίμυος. Έτσι, για τη μελέτη των θέσεων δέσμευσης των βενζοδιαζεπινών μεταξύ του διαφραγματικού και κροταφικού ιπποκάμπου χρησιμοποιήθηκε ο ευρέως φάσματος αγωνιστής των θέσεων δέσμευσης των βενζοδιαζεπινών, [3H]-flunitrazepam, σε μια αυτοραδιογραφική μελέτη. Επιπλέον, χρησιμοποιήθηκαν εξειδικευμένα φάρμακα, που δεσμεύονται σε συγκεριμένους υποτύπους του GABAA υποδοχέα, όπως το zolpidem (ειδικός αγωνιστής των GABAA υποδοχέων, που περιέχουν την α1-υπομονάδα), το etomidate (ειδικός θετικός αλλοστερικός ρυθμιστής των GABAA υποδοχέων, που περιέχουν τη β2-υπομονάδα) και το L-655,708 (ειδικός αντίστροφος αγωνιστής των GABAA υποδοχέων, που περιεχούν την α5-υπομονάδα) σε μια αυτοραδιγραφική κινητική μελέτη. Τα αποτελέσματα μας έδειξαν ότι οι τομές που προέρχονταν από τον ΚΙ συγκρινόμενες με αυτές από τον ΔΙ είχαν: Α) μειωμένη δέσμευση της [3H]-flunitrazepam στις CA1, CA3 και DG περιοχές, Β) μικρότερη χημική συγγένεια της δέσμευση της [3H]-flunitrazepam στη CA1 περιοχή, Γ) καμία διαφορά στον αριθμό των θέσεων δέσμευσης, Δ) μεγαλύτερες τιμές IC50 και EC50 για το zolpidem και το etomidate, αντίστοιχα και Ε) μικρότερες τιμές IC50 για το L-655,708. Συμπερασματικά, τα αποτελέσματά μας υποδεικνύουν διαφορετικές φαραμκολογικές ιδιότητες των υποτύπων του GABAΑ/ΒΖ υποδοχέα μεταξύ του ΔΙ και ΚΙ, ενώ επιβεβαιώνεται και ενισχύεται προηγούμενη μελέτη που υποδηλώνει ότι ο α1β2-υποτύπος του GABAA υποδοχέα επικρατεί στον διαφραγματικό ιππόκαμπο (ΔΙ), ενώ ο α2β1-υπότυπος κυριαρχεί στον κροταφικό ιππόκαμπο (ΚΙ). Η μελέτη αυτή είναι πιθανό να τυγχάνει ιδιαίτερης κλινικής αξίας, στην κατεύθυνση της ακριβέστερης ρύθμισης των αποτελεσματικών δόσεων των διάφορων μορίων που δρουν στις θέσεις δέσμευσης των βενζοδιαζεπινών των α1- και α2-υποτύπων του GABAA υποδοχέα. / The hippocampus in the rat appears grossly as an elongated structure with its long axis bending in a C-shaped manner from the septal nuclei rostrodorsally to the incipient temporal lobe caudoventrally. The long axis of the hippocampal formation is referred as the dorsoventral axis. Although hippocampus has been traditionally thought as a homogeneous structure, several studies have been demonstrated differences at several organization levels (from the behavioural to the cellular) between its dorsal (DH) and ventral (VH) pole. Pharmacological studies have shown that the α1-GABAA receptor subtype is associated with the sedative and anticonvulsant effects of benzodiazepines (BZs), whereas the α2-subtype is associated with the anxiolytic effects of BZs. Recent data have demonstrated a differential distribution of the GABAA receptor subunits between DH and VH, with the α1/β2 GABAA receptor subtype dominating in the DH and the α2/β1 subtype prevailing in the VH. We therefore study possible differences in the pharmacological properties and receptor binding parameters of the GABAA/BZ receptor subtypes between DH and VH, by examining: 1a) the specific binding of [3H]-flunitrazepam (BZ sites agonist), by using quantitative autoradiography, b) the kinetic parameters of [3H]-flunitrazepam specific binding, by using the “wipe off” technique and 2) the competitive displacement of [3H]-flunitrazepam binding by using zolpidem (a specific agonist of α1-subtype) and L-655,708 (a specific inverse agonist of α5-subtype) and the enhancement of [3H]-flunitrazepam binding by using etomidate (a selective positive modulator of β2- subunit), in an autoradiographical saturation kinetic study. Our results showed in VH compared to the DH: A) lower level of [3H]-flunitrazepam binding in CA1, CA3 and DG regions, B) higher KD value for [3H]-flunitrazepam specific binding in CA1 region and no differences in the Bmax value, C) higher IC50 and EC50 values for zolpidem and etomidate, respectively and D) lower IC50 values for L-655,708. In conclusion, the lower affinity of GABAA receptors for [3H]-flunitrazepam binding, the higher IC50 and EC50 values for zolpidem and etomidate, respectively, as well as the lower IC50 values for L-655,708 observed in VH compared to DH, support the evidence that the α1/β2-GABAA receptor subtype dominates in DH and the α2/β1-subtype prevails in VH and suggest differential pharmacological effects of the benzodiazepines in DH compared to VH, which could be of clinical relevence for the more accuate adjustment of the effective dose of α1- and α2-subtype specific BZ binding sites’ ligands.

Sömnstörningar beror på störningar av de faktorer som normalt leder till sömn, där individen har svårigheter att somna och upplever då sömnlösa nätter. Sömnstörningar är vanligt förekommande i befolkningen och förekommer i olika former där insomni (sömnlöshet) är den typ som detta arbete har baserats på. Insomni är ett tillstånd som kan behandlas med både det växtbaserade läkemedlet Valeriana och det bensodiazepinliknande läkemedlet Zolpidem. Valeriana (vänderot) är en flerårig ört där dess jordstam används för produktion av läkemedel. Valeriana förekommer i olika beredningar, har använts vid behandling av insomningsbesvär under flera hundra år och verkar ha en lugnande/hypnotisk effekt. Valeriana säljs även receptfritt. Zolpidem ingår i gruppen hypnotika och är ett sömnmedel som har snabbverkande effekt. Läkemedlet verkar på liknande sätt som bensodiazepiner, där den kemiska strukturen skiljer dessa läkemedel åt. Syftet med detta examensarbete är att undersöka vilket av dessa 2 läkemedel som mest effektivt förbättrar sömnen hos personer med insomni, genom att separat jämföra läkemedlen med placebo. Vidare bedöms om skillnader finns mellan läkemedlens biverkningar. Arbetet baserades på 6 relevanta studier som hittades genom sökning på databasen PubMed samt OneSearch via Linnéuniversitets bibliotek. Slutsatsen av examensarbetet är att Zolpidem mer effektivt förbättrar sömnen hos personer med sömnlöshet, när Zolpidem och Valeriana var sig har jämförts med placebo. Inga av läkemedlen hade några allvarliga biverkningar, läkemedlen hade också liknande biverkningar med undantag för enstaka sällsynta incidenter hos Zolpidem. Zolpidem hade en bibehållen effekt med tiden. Zolpidem rekommenderas för behandling av personer med sömnlöshet eftersom detta läkemedel behandlar symtomen mer effektivt. / Sleep disorders come from disruptions in factors that precedes sleep, where the individual has an inability to fall asleep and thus experiences sleepless nights.Sleep disorders are a common occurrence and come in different shapes where insomnia is the type this project will focus on. Insomnia is a condition that can be treated with both the herbal medicine Valerian and the drug Zolpidem that is similar to benzodiazepine.Valerian is a perennial herb where its earth stem is used in drug manufacturing. Valerian comes in different preparations, has been used in treatment of sleep difficulties during centuries and seems to have a hypnotic effect. Valerian is also a prescription free drug. Side effects due to the use of Valerian may be gastrointestinal symptoms such as nausea and abdominal pain. Overall side effects from use of this herbal are rare.Zolpidem is a hypnotic with a fast-acting effect. The drug works in similar ways to benzodiazepine but the chemical structure differs from benzodiazepine. Side effects that may occur include amnesia and sleep walking behavior. Increased anxiety, restlessness and mood swings are common side effects from use of Zolpidem.The purpose of this project is to investigate which of these two drugs are more effective at improving sleep in people with insomnia, by separately comparing the drugs to placebo. Further on assessments were made regarding the differences between the drugs side effects. This project is based on six relevant studies found through the database PubMed and OneSearch through the library of university of Linnaeus. Results of the studies showed that Valerian did not improve sleep compared to placebo in people with insomnia. Zolpidem, however, improved sleep in these people compared to placebo. No serious adverse events occurred with either of the drugs.This project concludes that Zolpidem is more effective at improving sleep in insomniacs, when Zolpidem and Valerian were individually compared to placebo. The drugs had similar adverse events, and none of them were serious. Zolpidem did however have a few rare incidents regarding adverse events. Zolpidem had a retained effect over time. Zolpidem is recommended for treating insomniacs since this drug has displayed greater efficacy in treating the symptoms.