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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Both cinnarizine and flunarizine are antihistaminic drugs that are mainly used for the control of vomiting caused by motion sickness (Todd and Benfield 1989; Towse 1980). Both drugs act by interfering with the signal transmission between the vestibular apparatus of the inner ear and the vomiting center of the hypothalamus. The disparity of signal processing between inner ear motion receptors and the visual senses is abolished, such that the confusion of the brain as to whether the individual is moving or standing is reduced. Both cinnarizine and flunarizine could be regarded as nootropic drugs because of their vasorelaxing abilities resulting from calcium channel blocking activity (Cook and James 1981). The major metabolic pathway in male rats is the oxidative N-dealkylation to form bis(4-fluorophenyl)methanol and a number of complementary metabolites of the cinnamylpiperazine moiety, of which hippuric acid is the main one (Meuldermans et al. 1983). In female rats and male dogs, however, hydroxy-flunarizine is the main metabolite, resulting from the aromatic hydroxylation of the phenyl ring of the cinnamyl moiety. Enterohepatic circulation of bis(4-fluorophenyl)methanol and hydroxy-flunarizine is proven by “donor–acceptor” coupling in rats; in bile and urine, these two metabolites are present mainly as glucuronides. The glucuronide of hydroxy-flunarizine is also the main plasma metabolite in dogs (Meuldermans et al. 1983).
Drug Therapy in Otology
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
The antihistamines are competitive antagonists of histamine at H1-receptors, and their main action is on the vomiting centre rather than on the chemoreceptor trigger zone. They have weak anticholinergic effects and may occasionally produce a dry mouth and blurred vision. Drowsiness, occasional insomnia and euphoria are side effects that have been reported. These central effects are accentuated with alcohol. Cinnarazine (Stugeron®) and cyclizine (Valoid®) are less sedating than promethazine teoclate (Avomine®). Cinnarizine has been used in the prophylaxis and treatment of Menière’s at a dosage of 30 mg three times a day. Cyclizine may be given in the acute attack orally or parentally at a dosage of 50 mg three times a day.
A patent review of mTOR inhibitors for cancer therapy (2011–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Han-Yue Qiu, Peng-Fei Wang, Min Zhang
Gino et al. from the Regents of the University of California discovered a novel category of compounds as mTORC1-specific inhibitors, which do not inhibit mTORC2 and produce negative side effects associated with mTORC2 inhibition. About 1600 small molecule human drugs were screened for mTOR protein binding at 10 μM by novel biolayer interferometry to identify potentially novel modulators of mTOR pathways. Among them, 16 compounds were identified that bound to mTOR protein in a dose-dependent manner from 100 nM to 100 μM. Then, the functional specificities for mTORC1 and mTORC2 of the binders were measured by S6Kinase and Akt phosphorylation assays. Fortunately, the repurposing research led to cinnarizine (1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine) (27) and hydroxyzine (2-[2-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]ethanol) (28), which dose-dependently inhibited mTORC1 specifically with both EC50 values of 500 nM while largely sparing mTORC2 activity. As cinnarizine and its analogs are already used as anti-histamines, this chemical scaffold has very extensive pharmacological and safety profiles [95]. All the biological results suggested cinnarizine and hydroxyzine have excellent potential to be developed as the first novel, specific, safe pharmacological mTORC1 inhibitors and may enter to the market in the future [96].
Cinnarizine as an alternative recommendation for migraine prophylaxis: a narrative review
Published in Expert Review of Neurotherapeutics, 2020
Mansoureh Togha, Fahime Martami, Mohammad Abdollahi, Mohammad Mozafari, Hamed Cheraghali, Pegah Rafiee, Maryam Shafaei
Apart from our recommendation to use cinnarizine in treating pediatric migraine headache, it already seems to be an acceptable migraine prophylactic drug for the adult population, though its efficacy on migraine-associated vertigo among patients who suffer from vestibular migraine and migraine with brainstem aura is more prominent and promising. This finding is in accordance with the fact that CIN, as a selective calcium channel blocker, is used for the prevention and treatment of vertigo [44] and previous research shows that it can effectively treat vertigos with various origins, either by itself or in combination with other drugs [45,46]. This finding is of interest in light of the possibility that patients who suffer from migraine-associated vertigo, may have a higher chance to benefit from CIN. In support of this hypothesis, a recently published systematic review, that explored the efficacy of the various treatment options for vestibular migraine prophylaxis, indicated that calcium channel blockers including cinnarizine were effective in reducing symptoms (headache and vertigo frequency) in 76.67% of patients [38].
Supersaturated lipid-based drug delivery systems – exploring impact of lipid composition type and drug properties on supersaturability and physical stability
Published in Drug Development and Industrial Pharmacy, 2020
Alexandra-Roxana Ilie, Brendan T. Griffin, Ruzica Kolakovic, Maria Vertzoni, Martin Kuentz, René Holm
Solubility determinations at 60 °C indicated that dose loading of celecoxib was increased by 71.8 to 172.8% in the tested LBDDS compared to ambient temperature solubility with the lowest solubilized dose in LCM (36.2 ± 2.8 mg/mL) and the highest in MCM + S (258.5 ± 51.2 mg/mL). The dose loading of cinnarizine increased between 55.0 and 196.0% in the tested LBDDS at 60 °C compared to ambient temperature, with the lowest dose solubilized in LCM + LCT + S (42.2 ± 0.3 mg/mL) and the highest in the corresponding MC systems, i.e. MCM + MCT + S (89.9 ± 8.7 mg/mL). For JNJ-2A, at 60 °C, the solubilization capacity of the tested LBDDS increased between 3.6 and 87.7% with the lowest solubilized dose observed for LCM (76.5 ± 2.9 mg/mL) and the highest for MCM + MCT + S (507.1 ± 28.4 mg/mL). Interestingly, in the case of MCM and MCM + S systems the solubility at 60 °C was quantitatively lower than the solubility at 37 °C, suggesting that no further gains in dose loading could be achieved at the higher temperature.