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An Overview of Experimental Methods
Published in Richard Beasley, Neil E. Pearce, The Role of Beta Receptor Agonist Therapy in Asthma Mortality, 2020
All of the aforementioned studies have involved acute effects of beta agonists. More recently, some studies have reported deterioration in lung function with long-term use of regular beta agonists.68 The underlying cause for such occurrences is not known, although they may relate to increases in bronchial hyperresponsiveness. However, not all studies with regular beta agonist use have been able to demonstrate deterioration in lung function,23,69 and it may relate to certain beta agonists, such as isoprenaline and fenoterol.22,23,68 Study designs to assess the underlying mechanism and incidence of potential deterioration in respiratory function are difficult to define. At present, such basic questions as what dosage constitutes regular use sufficient to downregulate beta receptors and duration of treatment, remain elusive. Studies with enantiomers instead of racemic mixtures may also be relevant in assessing this problem.70 Plainly it is of major importance with the introduction of new long-acting beta agonists, such as salmeterol and formoterol.
Adrenergic Agonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Dobutamine interacts with β and α receptors and was earlier thought being a selective β1 receptor agonist. It is similar in structure to dopamine. Both enantiomeric forms exist as a racemic mixture. The levo (−) isomer is an α1 receptor agonist while the dextro (+) isomer is an antagonist of α1 receptors. Both isomers have agonist effects on beta receptors although dextro isomer is more potent. Dobutamine produces more inotropic effects binding to the α1 receptors than the chronotropic effects on the heart. Cardiac output rises and then there is a change in the peripheral resistance. In some of the patients, there might be a significant increase in the heart rate and blood pressure and long-term effect is unclear. There might be a chance to develop tolerance. Dobutamine is used for a short-term period for treating decompensation of heart which happens in congestive heart failure or MI or after heart surgery. The onset of activity is fast, within 1–10 min and has a 2-min half-life (Brunton et al., 2011; Golan, 2012; Stevens et al., 2008). It penetrates well into CNS because of the absence of catechol in structure. Metabolism happens in the tissues and in the liver. The plasma half-life of the drug is approximately 2 min and excreted via urine (Rataboli, 2010; Florey, 2008).
Synthesis of Important Chiral Building Blocks for Pharmaceuticals Using Lactobacillus and Rhodococcus Alcohol Dehydrogenases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Marion Rauter, Simon Krebs, Gotthard Kunze
The separation of both enantiomers from a racemic mixture by chiral chromatography or chiral resolution as required after chemical synthesis is cumbersome and costly. Maximum yield is low with about 50% with regard to substrate concentration. Although optically active catalysts such as 2,2′–bis(diphenylphosphino)–1,1′–binaphthyl (BINAP) are available, they are expensive and require the use of physiologically problematic noble or transition metals (Sheldon, 2008).
Ibuprofen-based advanced therapeutics: breaking the inflammatory link in cancer, neurodegeneration, and diseases
Published in Drug Metabolism Reviews, 2021
Arun Upadhyay, Ayeman Amanullah, Vibhuti Joshi, Rohan Dhiman, Vijay Kumar Prajapati, Krishna Mohan Poluri, Amit Mishra
The commercially available Ibuprofen forms a racemic mixture that consists of two enantiomers, i.e. S (+)-Ibuprofen and R(−)-Ibuprofen in equal proportion (Nanau and Neuman 2010). Out of the two, S (+)-isoform presents a high inhibitory potential against the PGs as compared to a negligible potency of the (R)-isoform (Adams et al. 1976). However, it is evident in animal models that (R)-enantiomer is converted into (S)-isoform via a chiral inversion inside the body and starts showing some inhibition potential (Adams et al. 1976; Hutt and Caldwell 1983; Evans 2001). As shown in Figure 1, the standard Ibuprofen formulations are given orally, and hence they are supposed to be readily absorbed in order to provide rapid analgesia (Mehlisch et al. 2002; Dewland et al. 2009). Attainment of high Cmax in a shorter tmax leads to an increased absorption; in the case of Ibuprofen, few of its salts like Ibuprofen arginate, Ibuprofen lysine, and Ibuprofen sodium show a higher absorption (Schettler et al. 2001; Desjardins et al. 2002; Klueglich et al. 2005; Schleier et al. 2007). Besides oral formulations, Ibuprofen is also absorbed topically if applied through the skin for rheumatism of soft tissues or damages in subcutaneous layers (Trnavsky et al. 2004).
Comparative toxicity and toxicokinetic studies of oxiracetam and (S)-oxiracetam in dogs
Published in Xenobiotica, 2019
Tian-tian Liu, Xin-miao Guo, Zu-yuan Rong, Xiang-feng Ye, Jin-feng Wei, Ai-ping Wang, Hong-tao Jin
It has been more than twenty years since the discovery of oxiracetam (ORT, 4-hydroxy-2-oxo-1-pyrrolidine acetamide), a derivative of piracetam, which is a nootropic used for treating memory decline and various cognitive function disorders (Bottini et al., 1992; Mondadori et al., 1996; Nicholson, 1990; Villardita et al., 1992). Oxiracetam has also been associated with promising central nervous system protective effects, including in cerebrovascular impairment (Kometani et al., 1991), ischemic stroke(Wang et al., 2014), and brain injury(Yi et al., 2016). Recent studies have shown that oxiracetam can reduce cognitive injury at high altitude (Hu et al., 2017; Li et al., 2017) and was selected to be co-administered with nerve growth factor for the treatment of hypertensive cerebral hemorrhage (Sun et al., 2018). Oxiracetam has an asymmetric carbon, and its enantiomers are (S) -and (R)-ORT (Figure 1). It is used as a racemic mixture in clinical treatment. Studies have shown that (S)-ORT has high efficacy and is the active component of racemic oxiracetam (Fan et al., 2018; Li et al., 2017). To the best of our knowledge, most studies have focused on differences in the effects of ORT enantiomers from a pharmacological (Baumann & Eap, 2001; Kasprzyk-Hordern, 2010) or pharmacokinetic (Son et al., 2004; Wan et al., 2014; Zhang et al., 2015a) perspective. However, the in vivo toxicity and toxicokinetics of oral ORT and (S)-ORT have not yet been investigated. Accordingly, ORT and (S)-ORT were evaluated in acute and 90-day repeated-dose toxicity and toxicokinetic studies in dogs following oral exposure, as described herein.
Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy
Published in Journal of Psychoactive Drugs, 2019
Jennifer Dore, Brent Turnipseed, Shannon Dwyer, Andrea Turnipseed, Julane Andries, German Ascani, Celeste Monnette, Angela Huidekoper, Nicole Strauss, Phil Wolfson
Ketamine is available in two enantiomers: the S (+) and the R (−) configurations. The S isomer is estimated to be approximately twice as powerful as the R (Weber et al. 2004). There is controversy in distinguishing a pattern of different effects between the two. Current pharmacological preparations include an equimolar racemic mixture of the two enantiomers. S (+) ketamine has just come to market with FDA approval as a patented antidepressant nasal preparation for in-office psychiatric use.