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Piperazine
Published in Anton C. de Groot, Monographs in Contact Allergy, 2021
Piperazine is an organic compound that was introduced to medicine as a solvent for uric acid and later as an anthelmintic (antinematodal agent). It produces a neuromuscular block leading to flaccid muscle paralysis in susceptible worms, which are then dislodged from the gut and expelled in feces. Piperazine is used as alternative treatment for ascariasis caused by Ascaris lumbricoides (roundworm) and enterobiasis (oxyuriasis) caused by Enterobius vermicularis (pinworm). In pharmaceutical products, piperazine may be employed as piperazine adipate (CAS number 142-88-1, EC number 205-569-0, molecular formula C10H20N2O4) (1). Piperazine also has numerous non-pharmaceutical applications. In this chapter, only allergic reactions to piperazine from pharmaceutical use are presented. See also Chapter 3.292 Pyrazinobutazone and Chapter 3.259 Phenylbutazone.
Control of Human Intestinal Nematode Infections
Published in Max J. Miller, E. J. Love, Parasitic Diseases: Treatment and Control, 2020
Piperazine has been used for almost 30 years and still is widely used in many countries as an inexpensive popular anthelmintic. Initial studies in group treatments in Africa in 1954 proved to be well accepted by the patients, who observed the elimination of roundworms. The use of piperzine was reviewed by Goodwin.26 Its effectiveness is limited to A. lumbricoides and E. vermicularis at the doseage of 50 mg/kg day divided into 3 to 5 doses for 5 d.27 Several salts are used, such as hexahydrate, citrate, phosphate, adipate, and tartrate, all soluble in water and readily absorbed from the intestine. Because there is a wide range between the therapeutic and the toxic doses, drug reactions are uncommon. In a few cases, piperazine produces nausea, vomiting, and diarrhea. When a large amount of the drug is swallowed or when the drug accumulates in the organism, mainly in cases of renal insufficiency, toxic effects are seen with dramatic symptoms, which fortunately are transient and do not leave sequelae. These symptoms are due to the effect of piperazine on the myoneural mammalian junctions, causing a blocking effect. The symptomatology is muscular incoordination, ataxia, vertigo, speech difficulty, confused mental state, muscular weakness, and myoclonic contractions. It may produce or exacerabate epileptic seizures in predisposed patients. Piperazine is contraindicated in patients with renal or hepatic insufficiency and in epileptic patients.
Glycosaminoglycans
Published in Luke R. Bucci, Nutrition Applied to Injury Rehabilitation and Sports Medicine, 2020
Crolle and D’Este, from the 1st Medical Division of Guistinian Hospital in Venice, Italy, randomly divided 30 subjects with chronic osteoarthritis into two groups of 15 subjects each.1313 The placebo group received one intramuscular injection daily of piperazine/chlorbutanol for 7 d, followed by 14 d of oral placebo capsules. The treated group received 1 intramuscular injection daily for 7 d, followed by 1.5 g/d of oral glucosamine sulfate for 14 d. No other antiinflammatory or analgesic drugs were given during the study period. Both treatments exhibited significant and equivalent decreases in joint pain at rest, active movement, or passive movement after 7 d. Overall symptom scores also decreased similarly after 7 d. The time to walk 20 m, walking speed over 20 m, and restrictive function symptoms were also decreased similarly in each group after 7 d. However, after 21 d, the glucosamine group continued to improve, while the placebo group returned to baseline levels for pain, restricted function, time to walk Abbreviations: exptl = experimental group (administered glucosamine salts); ctrl = control group (administered placebo or standard therapy); GA = Glucosamine Hydrochloride; GS = Glucosamine Sulfate; Gl = Glucosamine Iodide; im = intramuscular injection; ia = intraarticular injection; po = per os (oral administration); rdb = randomized-order, double-blind; rsb = randomized-order, single-blind.
Design, synthesis, and biological evaluation of novel carbazole derivatives as potent DNMT1 inhibitors with reasonable PK properties
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Ennian Li, Kai Wang, Bei Zhang, Siqi Guo, Senhao Xiao, Qi Pan, Xiaowan Wang, Weiying Chen, Yunshan Wu, Hesong Xu, Xiangqian Kong, Cheng Luo, Shijie Chen, Bo Liu
By virtue of the favourable DNMT1 inhibitory activity and specificity, WK-22, WK-23, WK-27 were selected for further PK evaluation in Sprague-Dawley (SD) Rats with DC_517 used as the reference33. As shown in Table 2, WK-22 gave an AUC of 867.2 ± 15.9 h ng/mL and oral bioavailability of 27.0%, whereas WK-27 gave an AUC of 427.2 ± 60.0 h ng/mL and oral bioavailability of 1.8%. This is perhaps because the introduction of piperazine leads to the reduction of permeability and absorption into the blood. WK-23 displayed a favourable plasma exposure (AUC0-t = 1064.9 ± 121.2 h ng/mL) and an acceptable oral bioavailability (F% = 37.1 ± 1.7), which is equivalent to DC_517 (AUC0-t = 1022.7 ± 60.9 h ng/mL, F% = 38.7 ± 2.9). Most strikingly, the elimination half-life of WK-23 (T1/2 = 7.9 h) has an advantage over DC_517 (T1/2 = 6.7 h).
An updated patent review of monoacylglycerol lipase (MAGL) inhibitors (2018-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Giulia Bononi, Giulio Poli, Flavio Rizzolio, Tiziano Tuccinardi, Marco Macchia, Filippo Minutolo, Carlotta Granchi
Piperazine-based derivatives are widely reported in many patents concerning MAGL inhibitors [47]. In 2019, Benz et al. developed a series of piperazine derivatives, which may be useful in the treatment or prophylaxis of neuroinflammation, pain, cancer, mental disorders, and neurodegenerative diseases (such as MS, AD, PD, ALS), traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, or depression [48]. The general structure of these derivatives is characterized by the central 2-(piperazin-1-yl)quinazolin-4(3 H)-one scaffold, bearing different aromatic substituents linked to the carbonyl group belonging to the amide moiety of the piperazine ring. The newly synthesized compounds were subjected to enzymatic inhibition assays on recombinant wild-type MAGL enzyme to measure their IC50 values. In the spectrophotometric enzymatic assays, the inhibitors were tested at different concentrations (ranging from 25 μM to 1.7 nM) and 4-nitrophenylacetate (4-NPA) was used as the MAGL substrate, finally reading the absorbance at 405 nm due to the reaction product 4-nitrophenol [49]. The most promising piperazine-based MAGL inhibitors of this series showed IC50 values in the range of 3.0–5.0 nM (compounds 1–4, Figure 1), but the mechanism of inhibition of these compounds was not specified in the original document, although we could presume they are reversible inhibitors by observing their chemical structures.
Piperazine skeleton in the structural modification of natural products: a review
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Run-Hui Zhang, Hong-Yan Guo, Hao Deng, Jinzi Li, Zhe-Shan Quan
Piperazine is a part of numerous natural and synthetic molecules, with broad therapeutic potential. In addition to being a pharmacophore, piperazine is used as a linker/bridge between natural products and active structural molecules. This review summarises the research progress in the synthesis of natural product-piperazine derivatives in the past ten years, aiming to discover natural product piperazine hybrid compounds that may possess abundant biological activities. This will aid the scientific community in rationally design and develop novel, targeted, optimised, and diversified natural products-piperazine drugs for the treatment of multifactorial diseases. In conclusion, the piperazine group is widely used in for drug synthesis, attracting great attention from researchers worldwide, and its role cannot be ignored.