Rufinamide for use in the treatment of myotonia
A technology of rufinamide and carboxamide, applied in the field of rufinamide or its derivatives, can solve the problems of no congenital myotonia treatment, adverse side effects, etc.
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Embodiment 1
[0202] Purpose
[0203] To test whether rufinamide (RUF), lamotrigine (LTG) and lacosamide (LCM) could abolish myotonia induced by ClC-1 inhibition in rat soleus muscle.
[0204] method
[0205] animal handling
[0206] No experiments were performed on live animals, and all handling and killing of animals was in accordance with Danish animal welfare regulations and the local animal handling guidelines of Aarhus University. Contractility was measured in the soleus muscle after dissection of young 4-week-old male / female Wistar rats (65-75 g) obtained from the Janvier laboratory. All animals were fed ad libitum and maintained at constant temperature (21°C) and day length (12h).
[0207] Solutions and Compounds
[0208] The standard Krebs-Ringer solution used for incubation during the experiment contained (mM): 122NaCl, 25NaHCO 3 , 2.8KCl, 1.2KH 2 PO 4 , 0.6MgSO 4 , 1.27CaCl 2 and 5D-glucose. In all experiments, the solution was kept at 30 °C and heated with 95% O 2...
Embodiment 2
[0222] Purpose
[0223] To investigate whether three anticonvulsant drugs, rufinamide (RUF), lamotrigine (LTG), and lacosamide (LCM), reduce myotonia in human muscles.
[0224] method
[0225] human tissue
[0226] The use of human muscles was approved by the Danish Ethics Committee (Region Midtjylland, Committee 1) (ref. 1-10-72-20-13) and performed in accordance with the Helsinki Declaration. Informed consent was obtained from all subjects before inclusion. Muscles were obtained from 4 male subjects admitted at Skejby Hospital in connection with planned aortic aneurysm surgery. Isolation of subject tissues was performed as previously described (SkovM, De Paoli FV, Lausten J, Nielsen OB, Pedersen TH. Extracellular magnesium and calcium reduce myotonia in isolated ClC-1 chloride channel-inhibited human muscle. Muscle Nerve. 2015 Jan; 51( 1):65-71). After isolation, the tissue was transported to the university's laboratory (2 After equilibrating at 30°C for 10-20 min, ...
Embodiment 3
[0236] Purpose
[0237] Determine if drugs have additive or synergistic effects on myotonia.
[0238] method
[0239] As described in Example 1.
[0240] result
[0241] Effects of Combination Drugs
[0242] Rufinamide, lamotrigine, and lacosamide all reduced myotonia at concentrations within the free serum concentrations observed in patients. However, while lacosamide must be elevated above clinically accepted concentrations to abolish myotonia, the concentrations of lamotrigine and rufinamide required to abolish myotonia are well within the clinically accepted range.
[0243] To determine whether additive or synergistic effects could be observed when drugs were combined, the following experiments were performed with drug combinations: LCM-RUF, LCM-LTG, LTG-RUF and all three together. In all these experiments, rat soleus muscles were used.
[0244] Similar to either drug alone, significant reductions in AUC were observed with any drug combination. Therefore, by c...
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