1. G\u0130R\u0130\u015e<\/strong><\/p>\n Benzodiazepinler, gamaaminob\u00fctirik asit (GABA) sistemi (\u00f6ncelikle GABAA resept\u00f6r\u00fc) \u00fczerinde etki ederek, GABA varl\u0131\u011f\u0131nda klor\u00fcr kanal\u0131n\u0131n a\u00e7\u0131lma frekans\u0131n\u0131 artt\u0131rarak hiperpolarizasyona neden olan bir ila\u00e7 s\u0131n\u0131f\u0131d\u0131r. Bu \u00f6ncelikli olarak bir anksiyolitik, yat\u0131\u015ft\u0131r\u0131c\u0131 ve antikonv\u00fclsan etki ile sonu\u00e7lan\u0131r; bununla birlikte, bu ila\u00e7lar\u0131n endikasyonlar\u0131 anksiyete semptomlar\u0131n\u0131n y\u00f6netiminden kas gev\u015femesine kadar uzan\u0131r.<\/p>\n 1960 y\u0131l\u0131nda ilk BZD olan klordiazepoksitin piyasaya s\u00fcr\u00fclmesinden bu yana bir\u00e7ok t\u00fcrev sentezlenmi\u015f ve pazarlanm\u0131\u015ft\u0131r: bunlardan en \u00e7ok bilinenleri ku\u015fkusuz diazepam ve alprazolam\u2019d\u0131r.<\/p>\n Barbit\u00fcratlara g\u00f6re geli\u015ftirilmi\u015f g\u00fcvenlik profilleri nedeniyle, klinik pratikte kullan\u0131mlar\u0131 \u00f6nemli \u00f6l\u00e7\u00fcde artm\u0131\u015ft\u0131r; bununla birlikte, BZD’lere tolerans\u0131n ortaya \u00e7\u0131kmas\u0131 ve BZD’lerden geri \u00e7ekilme semptomlar\u0131n\u0131n g\u00f6z\u00fckmesi klinik bir ikilem ortaya koymu\u015f ve o zamandan bu yana bu ila\u00e7lar\u0131n y\u00f6netilmesini zorla\u015ft\u0131rm\u0131\u015ft\u0131r.<\/p>\n BZD t\u00fcrevi ila\u00e7lar\u0131 azaltmak endike oldu\u011funda bunu yapmak i\u00e7in literat\u00fcrde \u00f6nerilen birden \u00e7ok y\u00f6ntem vard\u0131r. Bunlar, \u201caniden kesme,\u201d \u201chaftal\u0131k %25 doz azaltma\u201d, \u201cher iki haftada bir g\u00fcnl\u00fck dozun sekizde biri ila onda biri oran\u0131nda azaltma\u201d ve \u201csemptom rehberli geri \u00e7ekilmeyi\u201d i\u00e7erir. Bununla birlikte, yava\u015f doz azalt\u0131m\u0131 ile bile, baz\u0131 hastalar anksiyete, ajitasyon ve huzursuzluk, duygu durum dalgalanmalar\u0131, uykusuzluk, haf\u0131za bozuklu\u011fu, bulant\u0131 ve kusma, ta\u015fikardi ve ciddi vakalarda n\u00f6betler gibi yoksunluk semptomlar\u0131 bildirilmektedir. B\u0131rakman\u0131n \u015fiddetini ve s\u00fcresini muhtemelen etkileyen \u00fc\u00e7 fakt\u00f6r \u015funlard\u0131r: ilac\u0131 kullan\u0131m s\u00fcresi, ilac\u0131n dozu ve ilac\u0131n yar\u0131 \u00f6mr\u00fc (k\u0131sa yar\u0131 \u00f6m\u00fcr, yoksunluk sendromunu k\u00f6t\u00fcle\u015ftirir).<\/p>\n Bug\u00fcne kadar BZD \u00e7ekilmesi s\u0131ras\u0131nda hastalar\u0131n iyilik halini artt\u0131rabilmek ad\u0131na \u00e7e\u015fitli ila\u00e7lar klinik deneylere konu olmu\u015ftur. BZD doz a\u015f\u0131m\u0131nda ya da giri\u015fimsel bir i\u015flem s\u0131ras\u0131nda olu\u015fturulan sedasyonun tersine \u00e7evrilmesi i\u00e7in kullan\u0131lan bir GABAA resept\u00f6r antagonisti olan Flumazenil, birka\u00e7 randomize kontrol \u00e7al\u0131\u015fmada ara\u015ft\u0131r\u0131lm\u0131\u015ft\u0131r. \u00c7al\u0131\u015fmalar, genellikle de\u011fi\u015fken dozlarda (1-4 mg\/24 saat) etkinlik de\u011ferlendirmesi yap\u0131lmakla beraber; bilindi\u011fi kadar\u0131yla, kat\u0131 bir azaltma protokol\u00fc izlenmeden flumazenilin BZD kullan\u0131m\u0131n\u0131 azaltmadaki etkinli\u011fini de\u011ferlendiren bir \u00e7al\u0131\u015fma yoktur.<\/p>\n Harrison ve arkada\u015flar\u0131n\u0131n \u00e7al\u0131\u015fmas\u0131nda Flumazenilin d\u00fc\u015f\u00fck dozda s\u00fcrekli inf\u00fczyon \u015feklinde uygulanmas\u0131 bolus \u015feklinde verilmesine g\u00f6re daha g\u00fcvenli oldu\u011fu g\u00f6sterilmi\u015ftir fakat kat\u0131l\u0131mc\u0131lara 30 saniyede uygulanan 1 mg flumazenil dramatik panik reaksiyonlar\u0131 ve ard\u0131ndan BZD yoksunluk semptomlar\u0131n\u0131 h\u0131zland\u0131rd\u0131\u011f\u0131 g\u00f6r\u00fclm\u00fc\u015ft\u00fcr. Bununla birlikte, BZD kullan\u0131m\u0131n\u0131 azaltma giri\u015fimleri, flumazenil grubunda daha ba\u015far\u0131l\u0131 olmu\u015ftur. Flumazenilin (0,4-0,5 mg) 20-25 dakikadan daha yava\u015f uygulanmas\u0131n\u0131n bile BZD kullan\u0131c\u0131lar\u0131nda pani\u011fi h\u0131zland\u0131rd\u0131\u011f\u0131 g\u00f6sterilmi\u015ftir.<\/p>\n Bu \u00e7al\u0131\u015fman\u0131n amac\u0131, 30 mg’l\u0131k terap\u00f6tik maksimum diazepam e\u015fde\u011ferinin \u00fczerinde ve alt\u0131nda alan kat\u0131l\u0131mc\u0131larda BZD kullan\u0131m\u0131n\u0131, yoksunluk semptomlar\u0131n\u0131 ve kullan\u0131m iste\u011fini azaltmak i\u00e7in d\u00fc\u015f\u00fck doz subkutan flumazenilin g\u00fcvenli\u011fi ve etkinli\u011fi hakk\u0131nda pilot veri toplamak ve gelecekteki \u00e7al\u0131\u015fmalar i\u00e7in \u00f6rneklem b\u00fcy\u00fckl\u00fc\u011f\u00fc hakk\u0131nda bilgi vermek olarak belirlenmi\u015ftir.<\/p>\n 2. METODOLOJ\u0130<\/strong><\/p>\n 2.1. Klinik Ko\u015fullar<\/strong><\/p>\n \u00c7al\u0131\u015fma, Currumbin Clinic (Currumbin, Queensland) ve Fresh Start Recovery Program’\u0131nda (Subiaco, Bat\u0131 Avustralya) hem yatarak hem de ayakta tedavi g\u00f6ren hastalar\u0131 i\u00e7eren, \u00e7ok b\u00f6lgeli, \u00e7ift k\u00f6r, randomize \u00e7apraz ge\u00e7i\u015fli bir \u015fekilde tasarlanarak y\u00fcr\u00fct\u00fclm\u00fc\u015f.<\/p>\n 2.2.Kat\u0131l\u0131mc\u0131lar<\/strong><\/p>\n Kat\u0131l\u0131mc\u0131lar hem yatarak tedavi g\u00f6ren hem de ayaktan tedavi g\u00f6ren hastalar olmak \u00fczere iki gruptan al\u0131nm\u0131\u015f. Yatan hastalar, deneme s\u00fcresi boyunca klinik personeli taraf\u0131ndan izlenirken, ayakta tedavi g\u00f6ren hastalar ise atanm\u0131\u015f bir bak\u0131c\u0131n\u0131n g\u00f6zetimi alt\u0131nda takip edilmi\u015f.<\/p>\n \u00c7al\u0131\u015fmaya; deneme s\u00fcresi boyunca BZD kullan\u0131mlar\u0131n\u0131 azaltmak amac\u0131yla, g\u00fcnl\u00fck BZD kullan\u0131m \u00f6yk\u00fcs\u00fc olan 28 kat\u0131l\u0131mc\u0131 \u00e7al\u0131\u015fmaya dahil edilmi\u015f.<\/p>\n Dahil etme kriterleri, \u00fc\u00e7 aydan uzun s\u00fcredir g\u00fcnl\u00fck BZD kullan\u0131m\u0131, g\u00fcnl\u00fck 10 mg diazepam e\u015fde\u011ferinden daha fazla g\u00fcnl\u00fck BZD kullan\u0131m\u0131 ve BZD’leri b\u0131rakma arzusu olarak belirlenmi\u015f.<\/p>\n D\u0131\u015flama kriterleri ise flumazenilin n\u00f6beti h\u0131zland\u0131rma olas\u0131l\u0131\u011f\u0131 nedeniyle epilepsi veya n\u00f6bet \u00f6yk\u00fcs\u00fc, \u015fu anda hamile olma veya emzirme ve 18 ya\u015f\u0131n alt\u0131nda olunmas\u0131 olarak belirlenmi\u015f.<\/p>\n 28 kat\u0131l\u0131mc\u0131dan her gruptan bir tane olmak \u00fczere toplam iki kat\u0131l\u0131mc\u0131 \u00e7al\u0131\u015fman\u0131n dahil etme kriterlerini ihlal etmeleri nedeniyle \u00e7al\u0131\u015fmadan \u00e7\u0131kar\u0131lm\u0131\u015f.<\/p>\n 2.3.\u00c7al\u0131\u015fma Tasar\u0131m\u0131<\/strong><\/p>\n \u00c7al\u0131\u015fma \u00e7ift k\u00f6r, randomize \u00e7apraz ge\u00e7i\u015fli olarak tasarlanm\u0131\u015f. T\u00fcm kat\u0131l\u0131mc\u0131lar, \u00e7al\u0131\u015fma s\u00fcresi boyunca ilk olarak flumazenil veya plasebo alacak \u015fekilde randomize edilmi\u015f. 8 g\u00fcn sonras\u0131nda da \u00e7apraz ge\u00e7i\u015f sa\u011flanm\u0131\u015f. Kat\u0131l\u0131mc\u0131lar maksimum g\u00fcnl\u00fck doz olmaks\u0131z\u0131n gerekti\u011finde 10 mg’a kadar diazepam talep etmekte \u00f6zg\u00fcr tutulmu\u015f. Diazepam talep ettiklerinde, kat\u0131l\u0131mc\u0131lar\u0131n, de\u011fi\u015ftirilmi\u015f bir Klinik Enstit\u00fc Geri \u00c7ekilme De\u011ferlendirme \u00d6l\u00e7e\u011fine-Benzodizepin (CIWA-B) g\u00f6re de\u011ferlendirilmeleri yap\u0131lm\u0131\u015f. Bu de\u011ferlendirmede, konsantre olma g\u00fc\u00e7l\u00fc\u011f\u00fc, h\u0131zl\u0131 kalp at\u0131\u015f\u0131, i\u015ftahs\u0131zl\u0131k, kayg\u0131, ba\u015f a\u011fr\u0131lar\u0131 ve g\u00f6zlemlenebilirli\u011fi de\u011ferlendiren alt\u0131 maddeden toplam iki veya daha fazla puan ald\u0131klar\u0131nda ila\u00e7 almalar\u0131na izin verilmi\u015f.<\/p>\n Flumazenil ilk grubu, \u00e7al\u0131\u015fman\u0131n birinci g\u00fcn\u00fcnde flumazenil alarak ba\u015flam\u0131\u015f ve 9. G\u00fcnde plaseboya ge\u00e7ilmi\u015f. Plasebo ilk grubu ise, ilk 8 g\u00fcn boyunca plasebo inf\u00fczyonu alm\u0131\u015f ve sonras\u0131nda 9. G\u00fcnden itibaren flumazenil inf\u00fczyonuna ge\u00e7ilmi\u015f (\u015eekil 1).<\/p>\n \u015eekil 1.<\/strong> Her iki tedavi grubu i\u00e7in zaman \u00e7izelgesi<\/p>\n 2.4.Sonlan\u0131m \u00d6l\u00e7\u00fcmleri ve De\u011ferlendirmeler<\/strong><\/p>\n \u00a0<\/strong>Sonlan\u0131m hedefleri, (1) diazepam ve di\u011fer BZD kullan\u0131m\u0131 i\u00e7in ba\u015flang\u0131ca g\u00f6re y\u00fczdesel azalma, (2) BZD yoksunluk skorunda ba\u015flang\u0131ca g\u00f6re y\u00fczdesel azalma, (3) BZD kullanma iste\u011fi skorunda ba\u015flang\u0131ca g\u00f6re y\u00fczdesel azalma, (4) tedaviyle ilgili advers olaylar (AO), (5) plasebo birinci grupta BZD kullan\u0131m\u0131ndaki de\u011fi\u015fiklikler olarak 5 ba\u015fl\u0131k alt\u0131na toplanm\u0131\u015f.<\/p>\n Bu Sonlan\u0131mlar<\/strong>;<\/p>\n (1,5) deneme s\u00fcresi boyunca herhangi bir yasad\u0131\u015f\u0131 BZD kullan\u0131m\u0131n\u0131 hesaba katan diazepam kay\u0131t sayfas\u0131 ve takip raporu formu kullan\u0131larak \u00f6l\u00e7\u00fclm\u00fc\u015f<\/p>\n (2) Yoksunluk belirtilerini hafif (1-20), orta (21-40), \u015fiddetli (41 \u201460) ve \u00e7ok \u015fiddetli (61 \u201480) olarak CIWA-B\u2019a g\u00f6re s\u0131n\u0131fland\u0131r\u0131lm\u0131\u015f<\/p>\n (3) K\u0131sa Madde kullanma iste\u011fi \u00d6l\u00e7e\u011fi<\/p>\n (4) AO rapor formlar\u0131 ile belirlenmi\u015f.<\/p>\n 2. ile 7. g\u00fcnler ve 10. g\u00fcn ile 15. g\u00fcn aras\u0131nda BZD kullan\u0131mlar\u0131 kaydedilmi\u015f (Plasebo veya flumazenil inf\u00fczyon ba\u015flang\u0131\u00e7 ve biti\u015f saatlerinde az da olsa varyasyon oldu\u011fu i\u00e7in inf\u00fczyon ba\u015flanan ve bitirilen g\u00fcnler de\u011ferlendirilmeye al\u0131nmam\u0131\u015f ilk \u00f6l\u00e7\u00fcmler ba\u015flang\u0131\u00e7tan sonraki g\u00fcn saat 08.00\u2019de yap\u0131lm\u0131\u015f). \u0130nf\u00fczyon ba\u015flang\u0131\u00e7 ve biti\u015f g\u00fcnlerinde (1., 4., 8., 9., 12., 16.) ise \u00e7ekilme, BZD kullanma iste\u011fi ve yasad\u0131\u015f\u0131 BZD kullan\u0131m\u0131 kayd\u0131 yap\u0131lm\u0131\u015f. OE’ler t\u00fcm kat\u0131l\u0131mc\u0131lar i\u00e7in olu\u015ftu\u011fu gibi rapor edilmi\u015f \u00c7al\u0131\u015fman\u0131n birincil amac\u0131, ba\u015flang\u0131\u00e7ta <30 mg ve> 30 mg diazepam e\u015fde\u011feri alan kat\u0131l\u0131mc\u0131larda flumazenilin detoksifikasyon s\u0131ras\u0131nda BZD kullan\u0131m\u0131n\u0131 azalt\u0131p azaltmayaca\u011f\u0131n\u0131 belirlemekmi\u015f. \u0130kincil hedefler, kat\u0131l\u0131mc\u0131lar\u0131 iki gruba ay\u0131rd\u0131ktan sonra yoksunluk belirtileri ve BZD isteklerindeki de\u011fi\u015fiklikleri ara\u015ft\u0131rmak ve bu, t\u00fcr\u00fcn\u00fcn ilk \u00e7al\u0131\u015fma tasar\u0131m\u0131 oldu\u011fundan, g\u00fc\u00e7 ve \u00f6rneklem b\u00fcy\u00fckl\u00fc\u011f\u00fc hesaplamalar\u0131 i\u00e7in birincil sonucun etki b\u00fcy\u00fckl\u00fc\u011f\u00fcn\u00fc belirlemekmi\u015f.<\/p>\n 2.5. Benzodiozepin dozu<\/strong><\/p>\n G\u00fcnl\u00fck BZD dozu, kat\u0131l\u0131mc\u0131n\u0131n almakta oldu\u011fu ana BZD\u2019ye g\u00f6re ba\u015flang\u0131\u00e7ta hesaplanm\u0131\u015f. Dozaj, G\u00fcney Avustralya Benzodiazepin e\u015fde\u011ferleri tablosuna dayal\u0131 olarak g\u00fcnl\u00fck diazepam e\u015fde\u011ferine d\u00f6n\u00fc\u015ft\u00fcr\u00fclerek belirlenmi\u015f. D\u00f6n\u00fc\u015f\u00fcm k\u0131lavuzu, 5 mg diazepam\u0131n 0,5 mg alprazolam, 0,25 mg klonazepam, 1 mg lorazepam, 30 mg oksazepam, 10 mg temazepam, 10 mg zolpidem ve 7,5 mg zopiklona e\u015fde\u011fer oldu\u011funu kabul etmektedir.<\/p>\n Kat\u0131l\u0131mc\u0131lar g\u00fcnl\u00fck kulland\u0131klar\u0131 benzodiazepin dozuna g\u00f6re <30 mg (d\u00fc\u015f\u00fck doz) ve \u2265 30 mg (y\u00fcksek doz) olarak ikiye ayr\u0131lm\u0131\u015f.<\/p>\n 2.6. Prosed\u00fcr<\/strong><\/p>\n T\u00fcm kat\u0131l\u0131mc\u0131lara, Go Medical Industries taraf\u0131ndan \u00fcretilen SpringFusor pompas\u0131 kullan\u0131larak subk\u00fctan olarak verilen 16 g\u00fcnl\u00fck bir s\u00fcre boyunca \u00e7apraz tasar\u0131ml\u0131 iki flumazenil ve iki salin inf\u00fczyonu verilmi\u015f. SpringFusor kullan\u0131m\u0131 ve kat\u0131l\u0131mc\u0131lar\u0131n inf\u00fczyon s\u00fcresince hareketli olmas\u0131na olanak sa\u011flayan bir d\u00fczene\u011fe sahipmi\u015f. Her bir inf\u00fczyon daha \u00f6nceki \u00e7al\u0131\u015fmalar\u0131 \u00f6rnek alarak 24 saatte 4 mg (\u00b1 %20) verecek ve 96 saat s\u00fcrecek \u015fekilde tasarland\u0131. Tedavi periyodu s\u0131ras\u0131nda, kat\u0131l\u0131mc\u0131lar, g\u00fcnl\u00fck ihtiya\u00e7lar\u0131na g\u00f6re tek seferde 10 mg\u2019a kadar olmak \u00fczere diazepam talep edebilmi\u015fler. Bu kat\u0131l\u0131mc\u0131lar modifiye CIWA-B’de iki veya daha fazla puan al\u0131rlarsa ila\u00e7 istekleri kar\u015f\u0131lanm\u0131\u015f ve g\u00fcnl\u00fck maksimum doz s\u0131n\u0131rlamas\u0131 belirlenmemi\u015f. T\u00fcm personel ve bak\u0131c\u0131lar, de\u011fi\u015ftirilmi\u015f CIWA-B’yi uygulayaca\u011f\u0131 konusunda e\u011fitilmi\u015f. Yatan hastan\u0131n diazepam\u0131, e\u011fitimli klinik personeli taraf\u0131ndan uygulanm\u0131\u015f ve kaydedilmi\u015f. Ayaktan hastalar\u0131n diazepam kullan\u0131m\u0131, e\u011fitimli se\u00e7ilmi\u015f bak\u0131c\u0131 taraf\u0131ndan uygulanm\u0131\u015f ve kaydedilmi\u015f. Kalan diazepam, do\u011fruluk ve kaydedilmemi\u015f yanl\u0131\u015f kullan\u0131m\u0131 belirlemek i\u00e7in kullan\u0131lan miktarla \u00e7apraz olarak kontrol edilmi\u015f. \u00c7al\u0131\u015fma boyunca, kat\u0131l\u0131mc\u0131lar, kendi rutin olarak kulland\u0131klar\u0131 ila\u00e7lar\u0131n\u0131 (BZD\u2019ler hari\u00e7) kullanmaya devam etmi\u015f ve di\u011fer ila\u00e7larda klinik ihtiyaca g\u00f6re de\u011fi\u015fiklikler yap\u0131lm\u0131\u015f. Kat\u0131l\u0131mc\u0131lar halihaz\u0131rda anti-epileptik ila\u00e7 kullanm\u0131yorsa, inf\u00fczyon s\u00fcresince g\u00fcnde \u00fc\u00e7 kez 100 mg fenitoin uygulanm\u0131\u015f.<\/p>\n 2.7. Randomizasyon<\/strong><\/p>\n Randomizasyon bilgisayar taraf\u0131ndan yap\u0131lm\u0131\u015f ve da\u011f\u0131l\u0131m 1:1 olarak belirlenmi\u015f. Klinik ve ara\u015ft\u0131rma personelinin, \u00e7al\u0131\u015fma s\u00fcresi boyunca kimin hangi ilac\u0131na ald\u0131\u011f\u0131na kar\u015f\u0131 bilgisi yokmu\u015f.<\/p>\n 3. SONU\u00c7LAR<\/strong><\/p>\n \u00a0<\/strong>Kat\u0131l\u0131mc\u0131 karakteristikleri<\/strong><\/p>\n Flumazenil ilk grubunda d\u00fc\u015f\u00fck doz (n = 5) ve y\u00fcksek doz (n = 8) ve plasebo ilk grubunda d\u00fc\u015f\u00fck doz (n = 6) ve y\u00fcksek doz (n = 7) kat\u0131l\u0131mc\u0131lar\u0131n\u0131n temel \u00f6zellikleri Tablo 1’de g\u00f6sterilmi\u015ftir.<\/p>\n Ortalama ya\u015f ve benzodiazepin kullan\u0131m s\u00fcresindeki farkl\u0131l\u0131klar\u0131n en \u00e7ok d\u00fc\u015f\u00fck doz gruplar\u0131 aras\u0131nda belirgin oldu\u011fu g\u00f6r\u00fclse de bu farkl\u0131l\u0131klar\u0131n istatistiksel olarak anlaml\u0131 olmad\u0131\u011f\u0131 bulunmu\u015f. Y\u00fcksek doz kohortundaki farkl\u0131l\u0131klar, b\u00fcy\u00fck \u00f6l\u00e7\u00fcde, flumazenil ilk grubunda ba\u015flang\u0131\u00e7ta 280 mg diazepam e\u015fde\u011feri kullanan tek bir kat\u0131l\u0131mc\u0131dan kaynaklanm\u0131\u015f. Flumazenil ilk y\u00fcksek doz grubu i\u00e7in g\u00fcnl\u00fck diazepam e\u015fde\u011feri kullan\u0131m 30 mg ila 280 mg aras\u0131nda de\u011fi\u015firken, plasebo ilk y\u00fcksek doz grubu 30 mg ila 100 mg aras\u0131nda de\u011fi\u015fmekteymi\u015f. \u0130lk flumazenil (40 mg) ve ilk plasebo (34 mg) gruplar\u0131nda medyan ba\u015flang\u0131\u00e7 \u200b\u200bdiazepam e\u015fde\u011feri kullan\u0131m\u0131n\u0131n benzer oldu\u011fu g\u00f6r\u00fclm\u00fc\u015f. Kat\u0131l\u0131mc\u0131lar\u0131n \u00e7o\u011fu BZD kullan\u0131m\u0131n\u0131 engellemeye \u00e7al\u0131\u015fm\u0131\u015f fakat ba\u015far\u0131s\u0131z olmu\u015ftur. Hi\u00e7bir kat\u0131l\u0131mc\u0131 yasa d\u0131\u015f\u0131 BZD kullan\u0131m\u0131 yoktu ve hepsine daha \u00f6nce bir psikiyatrik durum te\u015fhisi konmu\u015ftu. En yayg\u0131n olan\u0131 depresyon ve anksiyete bozukluklar\u0131yd\u0131.<\/p>\n G\u00fcnl\u00fck olarak d\u00fc\u015f\u00fck doz diazepam (<30 mg) kullanan grupta bazale g\u00f6re diazepam kullan\u0131m\u0131ndaki de\u011fi\u015fim, bazale g\u00f6re \u00e7ekilmedeki de\u011fi\u015fim ve bazale g\u00f6re BZD arzulamadaki de\u011fi\u015fim a\u00e7\u0131s\u0131ndan iki grup aras\u0131nda anlaml\u0131 fark bulunmam\u0131\u015f (p=0.429, 0.556, 0.476, s\u0131ras\u0131yla) (Tablo 2).<\/p>\n G\u00fcnl\u00fck olarak y\u00fcksek doz diazepam (\u2265 30 mg) kullanan grupta bazale g\u00f6re diazepam kullan\u0131m\u0131 de\u011fi\u015fimi Welch\u2019in t testi ile kar\u015f\u0131la\u015ft\u0131r\u0131lm\u0131\u015f. \u0130statistiksel olarak flumazenil ilk grubu (M= -75.30, SD=11.43), plasebo ilk grubuna (M=-44.85, SD=26.87), t(8.10) = -2.76, p=0.024, \u00e7ift tarafl\u0131, Hedge\u2019nin g\u2019si=-1.38) k\u0131yasla benzodiazepin kullan\u0131m\u0131nda daha fazla azalma g\u00f6stermi\u015f (%30.5, %95 GA [-54.85, -5.10] (Tablo 3).<\/p>\n G\u00fcnl\u00fck olarak y\u00fcksek doz diazepam (\u2265 30 mg) kullanan grupta , bazale g\u00f6re \u00e7ekilmedeki de\u011fi\u015fim ve bazale g\u00f6re BZD arzulamadaki de\u011fi\u015fim a\u00e7\u0131s\u0131ndan iki grup aras\u0131nda anlaml\u0131 fark bulunmam\u0131\u015f (p=0.836, 0.908, s\u0131ras\u0131yla) (Tablo 3).<\/p>\n \u00c7al\u0131\u015fman\u0131n g\u00fc\u00e7 analizi de\u011ferlendirildi\u011finde \u00e7al\u0131\u015fman\u0131n g\u00fcc\u00fc %61 (underpowered) olarak de\u011ferlendirilmi\u015f ve ilerideki \u00e7al\u0131\u015fmalar\u0131n %80 g\u00fcce ula\u015fmas\u0131 i\u00e7in gruplar\u0131n 20\u2019\u015fer ki\u015fi olmas\u0131 gerekti\u011fi \u00f6nerilmi\u015f.<\/p>\n \u00c7al\u0131\u015fmayla ilgili advers olaylar<\/strong><\/p>\n Deneme s\u0131ras\u0131nda ciddi bir advers olay kriterlerini kar\u015f\u0131lamayan toplamda 12 AO kaydedilmi\u015f. 12 AO’dan dokuzu flumazenil tedavisi s\u0131ras\u0131nda meydana gelmi\u015f (Tablo 4). Bunlardan \u00fc\u00e7 AO’\u0131n flumazenil ile ili\u015fkili oldu\u011fu ve ikisinin de prosed\u00fcrle ilgili oldu\u011fu belirlenmi\u015f. Plasebo ile tedavi s\u0131ras\u0131nda \u00fc\u00e7 AO meydana gelmi\u015f veikisi tedaviyle ilgili de\u011filmi\u015f ve biri belirsizmi\u015f.<\/p>\n 4.TARTI\u015eMA<\/strong><\/p>\n Bilindi\u011fi kadar\u0131yla bu \u00e7al\u0131\u015fma, s\u0131k\u0131 bir doz azaltma rejimine ba\u011fl\u0131 kalmadan flumazenil alan kat\u0131l\u0131mc\u0131larda BZD kullan\u0131m\u0131n\u0131 de\u011ferlendiren ilk randomize kontrol \u00e7al\u0131\u015fmad\u0131r. Sonu\u00e7lar, flumazenilin maksimum terap\u00f6tik g\u00fcnl\u00fck diazepam dozu e\u015fde\u011feri (30 mg) veya daha fazlas\u0131n\u0131 alan kat\u0131l\u0131mc\u0131larda kendi kendine talep edilen BZD kullan\u0131m\u0131n\u0131 \u00f6nemli \u00f6l\u00e7\u00fcde azaltt\u0131\u011f\u0131n\u0131 g\u00f6stermi\u015f. Bu bulgu, bazalde g\u00fcnl\u00fck 30 mg’dan az diazepam e\u015fde\u011feri alanlarda g\u00f6r\u00fclmedi, bu da tedaviden \u00f6nce 30 mg e\u015fde\u011feri diazepam alanlarda flumazenilin diazepam kullan\u0131m\u0131n\u0131 azaltmada daha az de\u011ferli oldu\u011funu d\u00fc\u015f\u00fcnd\u00fcrmektedir. Her iki grupta da yoksunluk veya kullan\u0131m iste\u011fi puanlar\u0131nda anlaml\u0131 bir fark g\u00f6r\u00fclmedi.<\/p>\n \u00d6nceki randomize kontroll\u00fc \u00e7al\u0131\u015fmalarda diazepam kullan\u0131m de\u011ferleri \u00e7al\u0131\u015fmalar aras\u0131nda de\u011fi\u015fiklik g\u00f6stermi\u015ftir: Gerra ve arkada\u015flar\u0131n\u0131n 2002\u2019deki \u00e7al\u0131\u015fmas\u0131nda2<\/sup>; 15-90 mg, Gerra ve arkada\u015flar\u0131n\u0131n 1993\u2019teki \u00e7al\u0131\u015fmas\u0131nda3<\/sup> 40-60 mg, Saxon ve arkada\u015flar\u0131n\u0131n 1997\u2019deki \u00e7al\u0131\u015fmas\u0131nda4<\/sup> 7.5-125 mg. Bu \u00e7al\u0131\u015fmalarda, %12 (n = 6\/50), %0 (n = 0\/36) ve %20 (n = 2\/10), terap\u00f6tik aral\u0131\u011f\u0131n (30 mg) alt\u0131nda diazepam e\u015fde\u011fer dozlar\u0131 kullanm\u0131\u015ft\u0131r. Ayr\u0131ca, flumazenilin etkinli\u011fini de\u011ferlendiren randomize olmayan kontroll\u00fc \u00e7al\u0131\u015fmalarda kat\u0131l\u0131mc\u0131lar\u0131n \u00e7o\u011fu veya tamam\u0131 terap\u00f6tik doz aral\u0131\u011f\u0131n\u0131 a\u015fm\u0131\u015ft\u0131r. \u00c7al\u0131\u015fmalar, grup olarak geri \u00e7ekilme puanlar\u0131nda d\u00fc\u015f\u00fc\u015fler g\u00f6sterdi; ancak d\u00fc\u015f\u00fck doz BZD kullanan kat\u0131l\u0131mc\u0131lar yeterince temsil edilmedi\u011fi d\u00fc\u015f\u00fcn\u00fclmektedir. Bu nedenle, bu pop\u00fclasyonda yoksunluk semptomlar\u0131n\u0131 hafifletmek i\u00e7in flumazenilin etkinli\u011fini \u00f6l\u00e7menin zor oldu\u011fu d\u00fc\u015f\u00fcn\u00fclm\u00fc\u015f. Bu nedenle bu \u00e7al\u0131\u015fma, terap\u00f6tik aral\u0131\u011f\u0131n alt\u0131nda diazepam e\u015fde\u011fer dozlar\u0131 kullanan kat\u0131l\u0131mc\u0131lar\u0131n %42’si ile farkl\u0131 bir demografiyi de\u011ferlendirmi\u015ftir. Bu \u00e7al\u0131\u015fman\u0131n bulgular\u0131 k\u00fc\u00e7\u00fck bir \u00f6rneklem b\u00fcy\u00fckl\u00fc\u011f\u00fc ile s\u0131n\u0131rl\u0131yd\u0131 ve gelecekte, de\u011fi\u015fen BZD kullan\u0131c\u0131lar\u0131nda flumazenilin etkinli\u011fini daha fazla ara\u015ft\u0131rmak i\u00e7in daha b\u00fcy\u00fck bir randomize kontroll\u00fc \u00e7al\u0131\u015fma y\u00fcr\u00fct\u00fclmelidir.<\/p>\n 5.KISITLILIKLAR<\/strong><\/p>\n \u00c7al\u0131\u015fma, gelecekteki \u00e7al\u0131\u015fmalar i\u00e7in \u00f6rneklem b\u00fcy\u00fckl\u00fc\u011f\u00fc hakk\u0131nda bilgi vermeyi ama\u00e7layan bir pilot \u00e7al\u0131\u015fma olsa da, \u00e7al\u0131\u015fman\u0131n d\u00fc\u015f\u00fck g\u00fcc\u00fc tip II hatalara (yanl\u0131\u015f negatif) yol a\u00e7abilece\u011finden, bulgular dikkatle yorumlanmal\u0131d\u0131r. Ayr\u0131ca, \u00e7al\u0131\u015fma s\u0131ras\u0131nda benzodiazepin kullan\u0131m\u0131 idrar tahlili ile do\u011frulanmad\u0131 ve yasa d\u0131\u015f\u0131 benzodiazepin kullan\u0131m\u0131 sadece kat\u0131l\u0131mc\u0131lar\u0131n kendi bildirimiyle belirlendi, bu nedenle nesnel \u00f6l\u00e7\u00fcmlerin eksikli\u011fi yoluyla \u00f6z bildirim yanl\u0131l\u0131\u011f\u0131 ortaya \u00e7\u0131kt\u0131. Gelecekteki ara\u015ft\u0131rmalar, flumazenilin etkili olabilece\u011fi bir pop\u00fclasyonu tan\u0131mlamak i\u00e7in hafif, orta ve \u015fiddetli yoksunluk semptomlar\u0131 olanlarda oldu\u011fu kadar, terap\u00f6tik aral\u0131\u011f\u0131n \u00fcst\u00fcnde ve alt\u0131nda g\u00fcnl\u00fck diazepam e\u015fde\u011ferlerini kullanan kat\u0131l\u0131mc\u0131larda flumazenilin etkinli\u011fini de\u011ferlendirmelidir. D\u00fc\u015f\u00fck doz BZD kullan\u0131c\u0131lar\u0131nda diazepam kullan\u0131m\u0131, yoksunluk ve kullan\u0131m iste\u011fi skorlar\u0131ndaki de\u011fi\u015fimler yeterince g\u00fcce sahip randomize kontroll\u00fc \u00e7al\u0131\u015fmalarla de\u011ferlendirilmelidir. Ayr\u0131ca, bu \u00e7al\u0131\u015fma yatarak veya ayakta tedavi g\u00f6ren kat\u0131l\u0131mc\u0131lar\u0131n pratikli\u011fine izin verirken, gelecekteki \u00e7al\u0131\u015fmalar, klinik olarak denetlenen bir detoks \u00fcnitesi gibi daha kontroll\u00fc bir ortamda tekrarlanabilir ve doz azaltma gibi alternatif yoksunluk y\u00f6ntemleriyle kar\u015f\u0131la\u015ft\u0131r\u0131labilir.<\/p>\n 6. SONU\u00c7LAR<\/strong><\/p>\n Veriler, d\u00fc\u015f\u00fck doz flumazenilin, tedaviden \u00f6nce en az \u00fc\u00e7 ay s\u00fcreyle terap\u00f6tik aral\u0131kta (>30 mg diazepam e\u015fde\u011feri) ve \u00fczerindeki dozlarda BZD kullanan bireylerde diazepam kullan\u0131m\u0131n\u0131 azaltt\u0131\u011f\u0131n\u0131 g\u00f6stermektedir. D\u00fc\u015f\u00fck doz BZD (<30 mg diazepam) alan kat\u0131l\u0131mc\u0131larda flumazenilin etkinli\u011fi g\u00f6sterilememi\u015f olsa da bu \u00e7al\u0131\u015fman\u0131n pilot bir \u00e7al\u0131\u015fma oldu\u011fu ve g\u00fcc\u00fcn\u00fcn (%61) bunu g\u00f6stermeye yetersiz olabilece\u011fi ak\u0131lda tutularak sonu\u00e7lar dikkatle yorumlanmal\u0131d\u0131r.<\/p>\n KAYNAKLAR<\/strong><\/p>\n Benzodiazepinler (BZD), hastalar taraf\u0131ndan en fazla yanl\u0131\u015f kullan\u0131m\u0131 yap\u0131lan ve suistimal edilen ila\u00e7lar aras\u0131nda bulunmaktad\u0131rlar. BZD’ler t\u0131bbi a\u00e7\u0131dan faydal\u0131 olmakla birlikte, potansiyel…<\/p>\n","protected":false},"author":1083,"featured_media":3564,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"inline_featured_image":false,"_lmt_disableupdate":"","_lmt_disable":"","footnotes":""},"categories":[1,10010,10014,10019],"tags":[10045,10046,10022,406],"class_list":["post-3558","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-genel","category-slider","category-akademik-blog-yazisi","category-tft","tag-benzodiazepin","tag-flumazenil","tag-tft","tag-toksikoloji"],"acf":[],"_links":{"self":[{"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/posts\/3558","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/users\/1083"}],"replies":[{"embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/comments?post=3558"}],"version-history":[{"count":0,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/posts\/3558\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/media\/3564"}],"wp:attachment":[{"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/media?parent=3558"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/categories?post=3558"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/tatd.org.tr\/toksikoloji\/wp-json\/wp\/v2\/tags?post=3558"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}![\"\"](\"https:\/\/tatd.org.tr\/toksikoloji\/wp-content\/uploads\/sites\/6\/2022\/10\/87a87c32dec3d6a3e5130831de5f1049.jpg\")
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