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Benzodiazepines as anxiolytics
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
Double-blind, placebo-controlled trials in GAD suggest that alpidem is an effective anxi-olytic that produces less sedation than full agonist benzodiazepines, such as lorazepam (Morton and Lader 1990; Diamond et al, 1991), with equivalent anxiolytic activity. In a comparative study against alprazolam (1.5 mg) alpidem (150 mg) equivalent efficacy was observed (Frattola et ad, 1994), but alpidem produced significantly less sedation and fewer withdrawal symptoms after treatment discontinuation. Although alpidem was approved for marketing, and indeed launched in some countries, such as France, it has since been withdrawn from sale. This was due to the occurrence of several cases of fatal hepatitis which appeared to be idiosyncratic reactions to the chemical moiety, as they are not seen with anxiolytics with the benzodiazepine structure or with the related compound, zolpidem.
Zolpidem high-dose abuse: what about the liver? Results from a series of 107 patients
Published in Expert Opinion on Drug Safety, 2019
Fabio Lugoboni, Antonio Mirijello, Laura Morbioli, Marco Faccini, Rebecca Casari, Salvatore De Cosmo, Antonio Gasbarrini, Giovanni Addolorato
Literature data show a relatively safe profile of BZDs in terms of liver toxicity [24], even at high doses [25]. In humans, ZLM is extensively hydroxylated by liver P450 cytochromes (CYP3A, CYP1A2, CYP2D6) [26,27]. As a consequence, liver toxicity is conceivable with ZLM abuse, particularly at high doses due to metabolic overwork. Moreover, alpidem, an imidazopyridine similar to ZLM, has been withdrawn from the market for its hepatotoxicity [28]. Although ZLM has been suspected to be one of the main contributing factors leading to death in a significant number of patients due to CNS toxicity and suicide [9], a causal relationship between ZLM and DILI has never been demonstrated. However, data on long-term ZLM abuse, particularly at high doses and for prolonged periods, are lacking.
Mesoporous particle-based microcontainers for intranasal delivery of imidazopyridine drugs
Published in Journal of Microencapsulation, 2018
Irina Marchenko, Tatiana Borodina, Daria Trushina, Irina Rassokhina, Yulia Volkova, Valerii Shirinian, Igor Zavarzin, Andrey Gogin, Tatiana Bukreeva
Anxiolytic–hypnotics agents are currently among the most frequently prescribed drugs worldwide, particularly in the Western world, and specifically the most prescribed psychoactive drugs. This trend started during the 1960s (Balter and Levine 1971) and continued with few modifications till present (Virani et al. 2012, Procyshyn et al. 2017). The most important change was done by almost total substitution of barbiturates and benzodiazepines with nonbenzodiazepines (non-BDZ), which are much safer in overdose, either accidental or intentional (Wagner and Wagner 2000, Fraser et al. 2013). The non-BDZ class includes the ‘Z-drugs’, for example, zolpidem, alpidem, etc., which became very popular with a large number of different molecules commercially available worldwide. Unfortunately, toxicity and side effects of these drugs, such as bioavailability and the mechanism of therapeutic effect, restricted broad non-BZD use among patients (Siriwardena et al. 2008). Thus, zolpidem is one of the most popular prescription sleep drugs can cause a host of crummy side effects including drowsiness, headache, muscle aches, stuffy or runny nose, memory loss, double vision, diarrhea, etc. (Inagaki et al. 2010, Mets et al. 2010, Gunja 2013). Alpidem was retired from the market because of rare but serious hepatotoxicity (Fau et al. 1994). Moreover, non-BDZ can cause tolerance, dependence and withdrawal symptoms (Licata and Rowlett 2008). Due to these restrictions, intense research was carried out to find novel formulations for non-BDZ anxiolytic–hypnotic agents in order to reduce their toxicity, side effects and to get more favourable toxicological profiles (Ries et al. 2014).