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Effects of Antithrombotic and Results of Drug Screening
Published in Josef Hladovec, Antithrombotic Drugs in Thrombosis Models, 2020
A very special class of calcium channel blocking agents with selective effect on the peripheral circulation includes flunarizine and similar agents (cinnarizine, lidoflazine).530 As shown in Figure 43, flunarizine had a marked stabilizing effect on the endothelium against desquamation by citrate at doses of 0.1 mg/kg both after oral and intravenous administration. The effect of a single dose is relatively long lasting. Cinnarizine and lidoflazine exerted similar effects in the endothelial test at a somewhat higher dose level (Figure 44). At a dose of 0.1 mg/kg p.o. flunarizine also prevented endothelial sloughing after 50 mg/kg i.v. calcium chloride, and if given at a still lower dose of 0.03 mg/kg orally, it significantly prevented the platelet sequestration after intravenous citrate (Figures 45, 46). In venous thrombosis (intestinal loop of rats, intravenous lactate, and stasis) no significant effect was noted just as in the electrical arterial thrombosis model. Similarly no effects on DIC after i.v. injection of ADP, on ex vivo platelet aggregation, and on prostacyclin generation were observed. The drug exerted no effect on the bleeding time in rats. To summarize, this type of drug has a marked favorable effect on the endothelium without possessing an antithrombotic activity probably due to the lack of the platelet-inhibitory component.
Blood Flow and Its Modulation in Malignant Tumors
Published in Neville Willmott, John Daly, Microspheres and Regional Cancer Therapy, 2020
As well as on smooth muscle cells some of these agents, particularly flunarizine, have effects on red blood cells that could be important for tissue oxygenation.92,93 When red blood cells are exposed to a low pH environment, such as they encounter when they traverse poorly oxygenated regions of tumors, their metabolism is inhibited so that they are unable to expel excess calcium ions.94 One consequence of this is that their plasma membrane becomes stiffened and spherical, leading to a marked increase in blood viscosity. The inhibition of calcium entry by flunarizine prevents this stiffening process thus improving tumor tissue perfusion.95
Complicated Linear Models
Published in John G. Wagner, Pharmacokinetics for the Pharmaceutical Scientist, 2018
An example is the flunarizine data of Wagner et al. [13]. Thirty milligram doses of flunarizine were administered to five epileptic patients and plasma samples were collected over a seventy-day period. The plasma samples were assayed for flunarizine at N.I.H. One of the subjects was designated as M03PS. Downslope data from 6 to 433 hours for this subject were fitted to a triexponential equation and disposition parameters for Model XX of Scheme 3.5 were derived as described in a later chapter. The Exact Loo- Riegelman method [10,11] for triexponential disposition [Equation (129)] was applied to all of the C, t data for this subject and produced the points shown in Figure 3.2. These points were fitted with the first-order Equation
Emerging drugs for the preventive treatment of migraine: a review of CGRP monoclonal antibodies and gepants trials
Published in Expert Opinion on Emerging Drugs, 2023
Marcello Silvestro, Ilaria Orologio, Mattia Siciliano, Francesca Trojsi, Alessandro Tessitore, Gioacchino Tedeschi, Antonio Russo
Other drugs used as preventive treatments are calcium channel antagonists and angiotensin blockers [47–49]. Evidence about the efficacy of calcium channel antagonists is weak and the mechanism of action is not fully understood although it may include the reduction of neural NO synthase activity, the blockade of serotonin release and inhibition of neurovascular inflammation, interference with neurovascular inflammation, or with the initiation and propagation of spreading depression [18,19]]. Among these flunarizine, that is among the most used preventive treatments in Europe but is not available in the United States, shows a favorable efficacy profile in patients with migraine without aura as well as in patients with migraine with aura. It has been hypothesized that the influence of flunarizine on dopamine D2 receptors could be associated with its anti-migraine effect, however the evaluation of dopamine D2 receptor binding potential (evaluated by Single Photon Emission Computed Tomography) was the same in patients and controls [50]. Although without worrisome safety concerns, some flunarizine AE such as fatigue, weight gain and mood changes make it not always well tolerated [51].
The effect of topiramate versus flunarizine on the non-headache symptoms of migraine
Published in International Journal of Neuroscience, 2023
Wei Li, Ruiting Liu, Weidong Liu, Guolei Li, Chunfu Chen
Previous studies have suggested that NHS of migraine is associated with DA [7,24]. Apomorphine, which is a DA receptor agonist, can enhance NHS of migraine, such as nausea, vomiting, and yawning [25], while metoclopramide, which is a DA receptor antagonist, can effectively relieve these symptoms [26]. In this study, flunarizine and topiramate significantly reduced both headache symptom and NHS. Flunarizine is a calcium channel blocker, while topiramate can also inhibit voltage-gated calcium channels [27]. Previous studies found that topiramate could block voltage-gated calcium channels, increasing the headache threshold and preventing the occurrence of migraine [28]. Experimental data have shown that calcium channel blockers can inhibit the uptake and release of DA, change in DA synthesis, and block the postsynaptic DA receptors [29]. Gracia-Naya et al. [30] suggested that the mechanism of flunarizine in treating migraine was related to antidopaminergic action at tubero-infundibular dopaminergic system level. Previous studies [31,32] have found that the affinity of dopamine receptor 2 (DRD2) was reduced after flunarizine treatment, and the decreased DRD2 affinity was not associated with headache and might be related to NHS of migraine. Animal studies [33] have found that administration of topiramate in mice can block the increase of DA in the nucleus accumbens induced by nicotine or cocaine, and this blocking effect may be directly related to the concentration of DA in the synaptic gap [34,35].
Factors determining the response to treatment in patients with vestibular migraine
Published in Neurological Research, 2022
Ayşın Kısabay Ak, Neşe Çelebisoy, Hüseyin Nezih Özdemir, Figen Gökçay, Gülsüm Saruhan Durmaz, Dilek Top Kartı, Hülya Ertaşoğlu Toydemir, Vildan Yayla, Ayşe İlksen Çolpak Işıkay, İrem Erkent, Pınar Özçelik, Gülden Akdal, Ceyla Ataç, Şebnem Bıçakcı, Eylem Ozaydın-Göksu, Feray Güleç Uyaroğlu
Patients were the ones who were treated with drugs recommended in migraine prophylaxis and followed up for at least a year thereafter. The same protocol had been performed in all. They had all been informed to avoid well-known triggers and have regular meals. Medical treatment included propranolol, amitriptyline, flunarizine, topiramate and venlafaxine depending on patients’ individual requirements. In patients with hypertension, without any lung disease, depression or diabetes mellitus, propranolol [7,10,16] was used at a maximum dose of 120 mg/d. In patients with depression or sleep problems, amitriptyline [7] was chosen as the first-line treatment and a maximum dose of 100 mg/d was used. Flunarizine was chosen in patients not having depressive symptoms [17] with a maximum dose of 10 mg/d. Topiramate was given up to 100 mg/d in patients not working in jobs requiring mental performance [17]. Venlafaxine [10] was used in patients with depression or anxiety at a maximum dose of 150 mg/d. The dosing schedule was individualized according to response to medications and the presence of side effects. Maximum dose of each drug was tried for 3 months to decide its efficacy. In the case of inefficacy, it was changed with another preventive drug of different class. After trial of a third drug if an adequate response is not gathered, a combination of two drugs of different class was attempted.