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Introduction / Patient Information Female patient in her 40s, married, in a stable relationship, employed. Suffers from schizophrenia and has been taking quetiapine (400 mg) for eight years. Clinical Presentation The patient was distressed by her unwanted genital and psychological arousals, that took place up to seven times a day. She explained that she felt aroused when in the presence of a man. She was making mistakes at work due to her physical and psychological arousal, often needed to go to the toilet and masturbate. Sometimes she masturbated so much and so vigorously that she hurt herself. Physical examination, laboratory findings, brain CT scan showed no abnormalities. After several consultations it was evident that her arousals were not painful, nor physically disturbing, but she felt guilt for having such feelings toward (what she felt to be) inappropriate men. She had strong religious believes and also thought that her condition was a kind of punishment. Treatment She was treated with valproate 600 mg ; and psychotherapy. The aim of psychotherapy was to diminish the guilt feelings, to explore her sexuality and to find more appropriate means at more appropriate time, how to satisfy her sexual urges. After 11 sessions she engaged in sexual activity three times a day and was more satisfied, and had less guilt and distress. Discussion This is a case of a women with psychological (schizophrenia), religious (guilt feelings) and pharmacological (quetiapine) burden. The differential diagnosis was between persistant genital arousal syndrome and hypersexuality. With pharmacotherapy (valproate) her impulsiveness (to act on sexual urges) was taken under control and with psychotherapy she was more willing to explore her sexuality, to think and talk (and even fantasize) about sexual matters. Conclusion / Take home message Sexual desire and sexual arousal are influenced by biological, iatrogenic (i.e. pharmacological), psychological, cultural and religious factors. It is important to take them all into account when considering aetiology of sexual problems. Also, it is important to combine pharmacotherapy, psychotherapy and counselling in the treatment of female sexual problems.

Wilson Hastalığı, otozomal çekinik geçiş gösteren, değişik derecelerde hepatik ve nöropsikiyatrik hastalıklarla sonuçlanabilen konjenital bir hastalıktır. Hastaların %20‟sinde bilişsel bozukluklar, kişilik bozuklukları ve duygu-durum bozuklukları gibi nöropsikiyatrik bozukluklar görülebilmektedir. Bu olgu sunumunda Wilson Hastalığı nede-niyle etkilenen beyin alanları, eşlik eden bipolar bozukluğu ve karma belirtilerin arasındaki bağlantının tartışılması amaçlanmıştır.

Under utvikling av nervesystemet er nevroner spesielt følsomme for ytre påvirkning, slik som legemidler eller oksidativt stress. Legemiddelbruk under svangerskap og hos små barn kan potensielt påvirke nevronal utvikling og gi uønskede langtidseffekter. Dette har blitt sett ved bruk av antiepileptika som lamotrigin (LTG) og valproat (VPA). Behandling av epilepsi er allikevel nødvendig under svangerskapet fordi ukontrollerte anfall kan være skadelig for både mor og foster. Det er derfor ønskelig å vite mer om hvilke mekanismer slike legemidler påvirker. I sikkerhetsfarmakologiske studier undersøkes potensielt skadelige effekter av et legemiddel på fysiologiske funksjoner, men de kan også gi ny kunnskap om de cellulære mekanismene som forårsaker slike effekter. Bruk av forsøkdyr er utbredt i slike studier, og det er ønskelig å erstatte dette med flere in vitro-modeller. Substanser som forstyrrer nevronal utvikling kan testes in vitro ved å se på påvirkning av nevrittutvekst i cellelinjer. Nevrittutvekst i cellelinjen PC12 er karakterisert og kan analyseres ved morfometrisk analyse. Dette skal kunne erstatte dyreforsøk og ble derfor brukt i denne oppgaven. NGF stimulerer PC12-celler via TrkA-reseptor til nevrittutvekst og ble brukt som positiv kontroll. Det ble også undersøkt om nevrittutvekst i PC12 er mediert via TrkB-signalering ved å bruke BDNF og TrkB-agonist, men PC12 viste seg ikke å være egnet til å studere dette. LTG og VPA ga økt nevrittutvekst i PC12. For å studere underliggende mekanismer bak dette ble det anvendt TrkA- og TrkB-reseptorantagonister. Dette viste at LTG og VPA påvirket nevrittutvekst via de samme signalveiene som nevrotrofinene. For ytterligere å belyse mekanismer som ligger bak nevrittutvekst, ble markørene p53 og MMP9 studert ved luciferaseassay og westernblotting. Både LTG og VPA så ut til å øke MMP9, og det antas at MMP9 er viktig i mekanismen bak nevrittutvekst. Luciferaseassay viste seg som et egnet supplement i screening i sikkerhetsfarmakologiske studier. Det er også viktig å studere om legemidler kan påvirke oksidativt stress, da dette kan gi skade på nevroner under utvikling. I produksjon av kroppens viktigste antioksidant glutation er enzymet GCS det hastighetsbestemmende trinnet. GCS ble derfor studert ved luciferaseassay. VPA ga økt, men LTG ga redusert GCS. Dette samsvarer med celledødstall for begge eksponeringer. For å undersøke relevansen av PC12-celler som erstatning for dyreforsøk ble forsøk utført i korncellekulturer fra kyllinglillehjerne. Studier av MMP9 viste lik trend i effekter av VPA og LTG som sett i PC12. Dette styrker grunnlaget for bruk av PC12 i sikkerhets- og basalfarmakologiske sudier som erstatning for forsøksdyr.

Amaç: Valproat ve elektrokonvülsif tedavinin bir arada kullanımı tartışmalı bir konudur. Duygudurum düzenleyici olarak kullanılan antikonvulzanların EKT sırasında nöbetin ortaya çıkışını olumsuz etkilemesinden endişe edilir. Bu araştırmada bipolar bozukluk manik epizot hastalarında elektrokonvülzif tedavi ile eşzamanlı kullanılan tam doz ya da azaltılmış dozdaki valproatın klinik etkileri incelenmiştir. Yöntem: Nisan 2010-Temmuz 2013 ayları arasında bir psikiyari hastanesinde bipolar bozukluk manik epizot tanısı ile elektrokonvülzif tedavi alan, epileptik olmayan, araştırma kriterlerine uygun ardışık 75 hastanın kayıtları incelenmiştir. Nöbet için gerekli enerji düzeyi, nöbet süresi, uygulanan elektrokonvülsif tedavi seans sayısı ve young Mani Ölçeği skorlarındaki değişim, EKT esnasında tam dozda valproat kullanan, % 40 azaltılmış dozda valproat kullanan ve valproat ya da başka bir antikonvülzan kullanmayan hasta grupları arasında karşılaştırılmıştır. Bulgular: Her üç grup karşılaştırıldığında geçirilen nöbet süreleri açısından kontrol grubu ile valproat doz ayarlaması yapılan grup arasında nöbet süreleri açısından fark saptanmamışken (p=0.078), kontrol grubu ile valproat doz ayarlaması yapılmayan grup arasında nöbet süreleri açısından fark saptanmıştır (p=0.038). Remisyona ulaşmak için gerek duyulan EKT seans sayısı tam doz valproat kullanan grupta anlamlı biçimde daha yüksek bulunmuştur. Valproat ile EKT’nin eşzamanlı kullanımı iyi tolere edilmiş, tam doz ya da azaltılmış doz valproat kullanan hastalarda ciddi bir yan etki izlenmemiştir. Tüm olgularda Young Mani skorunda anlamlı düşme ve klinik remisyon izlenmiştir. Tartışma: Valproatın EKT ile eşzamanlı kullanımı rutin EKT uygulamasına engel oluşturmamış ve koruyucu duygudurum düzenleyici tedavisine geçişi hızlandırmıştır. Bu bulguların doğrulanması ve kognitif yan etkilerin gruplar arasında kıyaslanabilmesi için ileriye dönük araştırmalara ihtiyaç bulunmaktadır.

Valproate is most commonly used to treat seizures in epilepsy. It is also used to treat manic or mixed episodes associated with bipolar disorder and to prevent migraine headaches. For decades it has been known that valproate increases the risk of major congenital abnormalities when taken during pregnancy. However, little has been known in regards to its effect on neurocognitive development. The last 5-10 years there has been an increasing amount of research in this area suggesting that valproate has an adverse effect on neurodevelopment in children after being exposed in utero. This survey has reviewed published research on the topic, and most of the reviewed articles were published in 2013. Studies suggest that being exposed to valproate in utero has an adverse effect on IQ, language, behavior and the prevalence of developmental disorders. There is increasing evidence that valproate might be more teratogenic than previously known, and hence there may be a need for updated guidelines regarding treatment with valproate for women in fertile age. More research is still needed to verify these findings and look into underlying mechanisms. There is also a need for studies with longer follow up to see if this tendency consists into adolescence and adulthood. Valproate is one of the antiepileptic drugs with best seizure control and for some patients the only efficient drug. Therefore, there is a consistent clinical dilemma. In light of newly published research it is important for clinicians to be updated on the topic when counseling a patient.

Valproate is most commonly used to treat seizures in epilepsy. It is also used to treat manic or mixed episodes associated with bipolar disorder and to prevent migraine headaches. For decades it has been known that valproate increases the risk of major congenital abnormalities when taken during pregnancy. However, little has been known in regards to its effect on neurocognitive development. The last 5-10 years there has been an increasing amount of research in this area suggesting that valproate has an adverse effect on neurodevelopment in children after being exposed in utero. This survey has reviewed published research on the topic, and most of the reviewed articles were published in 2013. Studies suggest that being exposed to valproate in utero has an adverse effect on IQ, language, behavior and the prevalence of developmental disorders. There is increasing evidence that valproate might be more teratogenic than previously known, and hence there may be a need for updated guidelines regarding treatment with valproate for women in fertile age. More research is still needed to verify these findings and look into underlying mechanisms. There is also a need for studies with longer follow up to see if this tendency consists into adolescence and adulthood. Valproate is one of the antiepileptic drugs with best seizure control and for some patients the only efficient drug. Therefore, there is a consistent clinical dilemma. In light of newly published research it is important for clinicians to be updated on the topic when counseling a patient.

Klinisch prospektive Studie zur Überprüfung, ob die Einnahme von Valproat zu einer verminderten zentralen Reflexkontrolle führt, die die Enuresisneigung bei Valproateinnahme erklären könnte.

Valproat je u kliničkoj praksi primjenjen kao antiepileptik i stabilizator raspoloženja, rjeđe za liječenje atipične depresije sa značajnom hipersomnijom, a također se koristi za liječenje migrenozne glavobolje i shizofrenije. Dermatološke nuspojave psihofarmaka najizraženije su u skupini stabilizatora raspoloženja, antiepileptika. Valproat je povezan s pojavom stomatitisa i kožnog leukoklastičnog vaskulitisa. Prijavljen je i slučaj psoriaziformnog osipa kod pacijenta liječenog valproatom. Nadalje dermatološke nuspojave valproata uključuju prolaznu alopeciju (2, 6% do 12%), prorijeđenje kose, promjene boje kose i rijetko osipe. Valproat je također povezan s Stevens-Johnsonovim sindromom i toksičnom epidermalnom nekrolizom TEN, s mogućim letalnim ishodom. Značajno je istaknuti da su alergijske reakcije na valproat znatno rjeđe nego kod drugih stabilizatora raspoloženja iz skupine antiepileptika. Vaskulitis je upala i nekroza stijenke krvnih žila (arterije, vene i kapilare). Uzrok može biti infektivni agens, mehanička trauma, radijacija ili toksini ; često se uzrok ne može prepoznati ; u etiopatogenezi se smatra da bi mogli biti odgovorni i imuni mehanizmi, npr. taloženje imunih kompleksa, izravni utjecaj cirkulirajućih protutijela itd. Leukocitoklastični vaskulitis je oblik hipersenzitivnog angiitisa. Pojavljuje se najčešće u koži u obliku lezije koja se opisuje kao palpabilna purpura. Mikroskopski se uočava fibrinoidna nekroza malih krvnih žila s infiltratom limfocira i ekstravazacija eritrocita. Pacijentica I.B.(35) se zaprima u Kliniku za kožne i spolne bolesti KBC-a Split s razvijenom kliničkom slikom leukocitoklastičnog vaskulitisa nakon ambulantnog pregleda i kontrole. Od treće godine života u neurološkom je tretmanu poradi epilepsije kompleksne simptomatologije. Obradom i isključenjem ostalih uzroka, dokazana je međusobna povezanost vaskulitisa i valproata, a klinička slika manifestirala se bez zahvaćanja unutarnjih organa. Iako je vrlo rijetka cilj nam je ukazati i skrenuti pozornost na mogućnost pojave ove nuspojave, poglavito stoga što neprepoznata i nedovoljno ozbiljno shvaćena, a popraćena sa zahvaćanjem unutarnjih organa, može progredirati do fatalnog ishoda.

This study investigates the effect of VPA on proliferation and migration in human coronary vascular cells. Methods and results: The theoretical clinical relevance of the data is estimated with a SI/MPL-ratio, which is defined as the relationship between a significant effect in vitro (SI) and the maximal plasma level in vivo (MPL). Cell culture: HUVEC, human umbilical endothelial cells; HCAEC, human coronary artery endothelial cells; HCMSMC, human coronary media smooth muscle cells. Proliferation assay: HUVEC, HCAEC, and HCMSMC were seeded as described. VPA was added in six different concentrations ranging between 50 and 300 µg/ml. At day 6 the cell number was calculated in relation with the cell number at day 1. Cell toxicity: Cytotoxic effects of VPA were studied in concentrations ranging from 50 to 300 µg/ml. Migration assay: Migration of HCMSMC after incubation with VPA in concentrations ranging from 50 to 300 µg/ml was studied for a period of 24 h. Proliferation assay: Strong dose-dependent antiproliferative effects were detected after 5 days of incubation with all the three tested cell types. In HUVEC, significant antiproliferative effects were found with VPA in concentrations of 100 µg/ml (P < 0.05, SI/MPL-ratio: 1.0) and more. In HCAEC and HCMSMC, significant antiproliferative effects were detected after incubation with VPA in the concentrations of 50 µg/ml (HCAEC: P < 0.01, SI/MPL ratio: 0.5; HCMSMC: P < 0.001, SI/MPL-ratio: 0.5). Migration assay: No effect on cell migration was detected after incubation of HCMSMC for a period of 48 h with VPA in concentrations ranging from 50 to 300 µg/ml. Cell toxicity: In HUVEC, HCAEC, and HCMSMC significant toxic effects were detected in all the VPA concentrations studied. Conclusion: Significant dose-dependent antiproliferative effects of VPA with SI/MPL ratios of 0.5 identify the drug as a promising candidate for both systemic and local therapy, such as drug eluting stents, of postinterventional restenosis.

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Histones and their N and C terminal tails undergo different covalent modifications that regulate gene transcription. Among these histone modifications are methylation, ubiquitinilation, SUMOylation, ADP- ribosylation, phosphorylation, proline izomerization, deimination and acetylation. Histone acetylation is regulated by histonacetyltransferases (HATs) and histondeacetylases (HDACs). The balance between acetylation/deacetylation influences chromatin condensation and thus regulates gene transcription. Acetylation balance is disrupted in many human cancers and this fact can contribute to the development of malignant diseases. Histondeacetylase inhibitors (HDACi) can restore this acetylation imbalance. One of these HDACi is valproic acid (VPA) which has been used in treatment of epilepsy for decades. VPA shows antitumour effect in many studies. Decreased expression of n-myc oncoprotein, inhibition of tumour growth and angiogenesis are one of these anticancer effects observed in neuroblastoma cell lines after treatment with VPA. Despite the fact that exact mechanism of antitumour effect of VPA remains unclear, one of the most important mechanisms is hyperacetylation of histone H3 and H4. It is shown in this work that VPA increases acetylation of histones H3 and H4 in human neuroblastoma cell lines...

Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation and inhibition of topoisomerase II. Ellipticine was also found to form covalent DNA adducts mediated by its enzymatic activation with cytochromes P450 (CYP) and peroxidases. The next study demonstrated increasing formation of these ellipticine-DNA adducts by histone deacetylase inhibitor valproate (VPA) in neuroblastoma cells. This phenomenon correlates with increasing cytotoxicity of ellipticine induced by this histone deacetylase inhibitor. This observation can be explained by several mechanisms. One of them can be loosening the structure of chromatine, which leads to accessing DNA for modification. Another one is the effect of VPA on activities and expression of enzymes metabolizing ellipticine. This study was aimed to test the second hypothesis. Since VPA has been shown to be metabolized by similar enzymes as ellipticine is, we have studied the effect of VPA (i) on oxidation of ellipticine by cytochromes P450 and peroxidases, (ii) on activities of the CYP enzymes, which significantly participate in oxidation of ellipticine (CYP1A, CYP3A) and (iii) on expression of enzymes oxidizing ellipticine (CYP1A1, CYP3A4, lactoperoxidase). Oxidation of ellipticine in vitro by model...

Validerat; 20101217 (root)

Znakovi upale gušterače kod djece slični su onima u odraslih. poremećeno opće stanje, bolan trbuh, povraćanje, povišene serumske amilaze.također se podudaraju načela intenzivnog liječenja kao i indikacije za kirurški zahvat.među najčešće uzroke pankreatitisa u djece ubrajaju se nuspojave pojedinih lijekova, pa tako i natrijeva valproata kojis e dugo koristii u liječenju epilepsije.

Bipolar disorder involves dysfunction in gamma amino butyric acid (GABA)/glutamatergic systems and neural circuits that regulate cognitive processing. Valproate, a mood stabilizing anticonvulsant, modulates GABA/glutamate and shows neuroprotective effect. Electroencephalographic oscillatory activity assessment is an alternative brain imaging technique with high time resolution. It presents integrative brain functioning. We aimed to assess the oscillatory responses of patients with bipolar disorder in euthymic state of bipolar disorder and the changes after treatment with valproate. Event related potentials to visual odd-ball paradigm in 10 euthymic medication free, bipolar patients were measured before and after 6 weeks of valproate monotherapy and compared with sex- and age-matched healthy controls. Delta frequency bands, as representative of signal detection and decision-making, were obtained by digital filtering. At baseline, patients showed higher delta responses to target stimuli in all but significantly left frontal channels in comparison to controls. After 6 weeks of treatment, delta responses decreased significantly in central frontal (Fz) (p: 0.028), left frontal (F3) (p: 0.028), left (T3) (p: 0.015), right anterior (T4) (p: 0.011), and left posterior temporal (T5) (p: 0.011) channels compared to baseline and became no different to the controls, which did not differ between two assessments. The findings point to a diffuse increase in low frequency electrical activity which was prominent in the left frontal location in euthymic patients with bipolar disorder. Reduction of the electrical activity of the left frontal and bilateral anterior temporal areas with treatment may be through modulation of glutamatergic and GABAergic mechanisms and indicative of valproate's neuroprotective effect. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Es wurde die Wirkung von Levetiracetam auf Zellzahlen, Thrombin-Bildung, Fibrinogen-FITC-Bindung und P-Selektin Expression (CD62P) bei 12 Probanden untersucht. Der Versucht wurde unter Levetiracetam 1000 mg, Valproat 500 mg und Placebo durchgeführt. Vor und nach den Prüfsubstanzen gab es keinen Unterschied in der Zellzahl. Die Werte vor und nach Levetiracetameinnahme bei den Thrombozytenfunktionen zeigen keine signifikanten Unterschiede. Nach Valproateinnahme kommt es zu einer signifikanten Steigerung der P-Selektin Expression (p < 0,017) und zu einem signifikanten Abfall (p < 0,012) bei Fibrinogen-FITC-Bindung. Kein Einfluss war für die Thrombin-Bildung gesehen worden. Die Wirkung von Valproat auf die Koagulation und Thrombozyten war bereits durch klinische Beobachtungen bekannt. Mit dieser Studie können die pathophysiologischen Grundlagen genauer erklärt werden. Dagegen konnte in unserer Studie gezeigt werden, dass Levetiracetam keine Wirkung auf die Blutzellzahl und Thrombozytenfunktion gehabt hat. Die Ergebnisse haben Auswirkungen auf die Wahl des Antiepileptikums bei Patienten mit Gerinnungsstörungen.

Titelblatt und Inhaltsverzeichnis Einleitung Herleitung der Aufgabenstellung Material und Methode Ergebnisse Diskussion Zusammenfassung Tabellen- und Abbildungsverzeichnis Literaturverzeichnis Danksagung Hinweise zur Veröffentlichung Lebenslauf Erklärung an Eides statt, Migräne ist die häufigste neurologische Erkrankung, die gekennzeichnet ist durch rezidivierenden, meist halbseitigen Kopfschmerz und vegetativen Begleiterscheinungen. Durch Einführung der Triptane konnte die Akuttherapie deutlich verbessert werden, jedoch haben Studien gezeigt, dass nur 5% der Patienten eine Prophylaxe erhalten, obwohl 50% der Patieten eine Prophylaxe bräuchten. Durch die Entdeckung der Wirksamkeit der Valproinsäure steht ein weiterer Wirkstoff zur Prophylaxe zur Verfügung. Studien mit einer täglichen Dosis von 300-1500mg/d haben die Wirksamkeit des Medikamentes bewiesen. Eine abschließende Dosisempfehlung konnte bisher nicht gegeben werden. Die Nebenwirkungsrate steigt ab einer Dosierung >1000mg/d deutlich an. Hier wurde erstmals die Korrelation zwischen dem Serumspiegel der Valproinsäure und der oralen Dosis sowie die Korrelation zwischen dem Serumspiegel und der Wirksamkeit untersucht. Die offene Studie in einer Tertiärambulanz schloss 52 Migräne-Patienten mit und ohne Aura ein. Die Auswertung erfolgte anhand eines Kopfschmerzkalenders und die Serumspiegelkontrollen fanden als Baseline, nach drei und nach sechs Monaten statt. Die Einteilung der Patienten erfolgte zunächst in drei Dosisgruppen (900mg/d). Es zeigte sich für die Anzahl der Migränetage in den Untersuchungszeiträumen eine Verbesserung gegenüber Baseline. Das subjektive Befinden wurde mit 20-30% Verbesserung angegeben. Es zeigte sich eine signifikante Verbesserung der Migräneattacken aller Gruppen gegenüber Baseline, jedoch nicht untereinander. Daraufhin wurden Serumspiegel untersucht und zwei Patientengruppen mit einem Serumspiegel 50µg/ml untersucht. Es zeigte sich keine Korrelation zwischen Wirkung und Serumspiegel und zwischen oraler Dosis und Serumspiegel. Bei der Anzahl der Migräneattacken und der Migränetage zeigte sich ein signifikanter Unterschied gegenüber Baseline und die Patientengruppe mit dem Serumspiegel, Migraine is the most frequent neurological disease, characterized by periodical unilateral headache with vegatative concomitants. Through the establishing of the triptanes the acute therapy could be improved significantly. But studies have shown that only 5% of patients received a prophylaxis although 50% needed. Through the stumble on efficacy of valproic acid a new drug for prophylaxis is available. Studies have shown the efficacy of doses between 300-1500mg/d. A concluding recommendation couldn´t be given. The side-effects raise upon a dosage over 1000mg/d. In this study the correlation between serum level of valproic acid and oral dosage and the correlation between serum level and efficacy has been tested for the first time. This open study included 52 patients with migraine with and without aura. The evaluation was made with a headache calendar and the measurement of serum valproic acid levels for baseline, after 3 month and after 6 month. The patients were distributed into 3 groups (900mg/d). There was an improvement for migraine days against baseline. The condition was increased by 20-30%. There was a significant improvement in migraine attacks against baseline but not between the groups. Two groups of serum levels were investigated, 50 µg/ml. There was no correlation between dosage and serum level and no correlation between serum level and efficacy. The number of migraine attacks and migraine days was significant better to baseline and the low serum level group was significantly better than the other group. A final dosage recommendation cannot be given, but by the german society of neurology and the german headache and migraine society valproic acid is recommended as a first choice drug in a dosage of 500-600mg/d. A test of serumlevel is only recommended when the compliance is unclear.