Pharmacology of lacosamide: From its molecular mechanisms and pharmacokinetics to future therapeutic applications

Carona, Andreia; Bicker, Joana; Silva, Rui; Fonseca, Carla Polo; Falcão, Amílcar; Fortuna, Ana

doi:10.1016/j.lfs.2021.119342

Cited by 20 publications

(17 citation statements)

References 87 publications

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“…The extent to which the unwanted reactions linked to the LCS treatment was explained by its on the magnitude, gating, and V hys of I K(A) and thus warrants further investigation. Findings from the present study tend to be informative as they highlight the proof-of-concept that needs to be taken into consideration since the wide spectrum of LCS's beneficial effects has been clinically observed [1][2][3][4][5][6][7][9][10][11][12][13][14][15][16][17][18][19][20][21]24,25,32].…”

Section: Discussionmentioning

confidence: 97%

“…From the present observations, we show that LCS shifted the inactivation curve of I K(A) in the rightward direction, suggesting that it interacts with channels in the inactivated state. Consequently, neither the resting membrane potential nor the magnitude of I Na could be seriously altered by its inhibitory effect on I K(A) , although it per se inhibited I Na directly [27][28][29][30][31][32]57]. It has been established that the K V channels, such as K A channels, are crucial in shaping action potentials.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, a previous report by Hagenacker et al (2013) has shown the ability of LCS to reduce analgesic effects and limit the effect on I Na inhibition in dorsal root ganglion neurons in a model of peripheral neuropathic pain [26]. Therefore, it is worthwhile to reappraise the ionic mechanism of LCS actions in varying types of transmembrane ionic currents, although the voltage-gated Na + (Na V ) channels were, until recently, focused on its therapeutic effectiveness [27][28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

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Evidence for Inhibitory Perturbations on the Amplitude, Gating, and Hysteresis of A-Type Potassium Current, Produced by Lacosamide, a Functionalized Amino Acid with Anticonvulsant Properties

Cho

Chuang

2022

IJMS

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Lacosamide (Vimpat®, LCS) is widely known as a functionalized amino acid with promising anti-convulsant properties; however, adverse events during its use have gradually appeared. Despite its inhibitory effect on voltage-gated Na+ current (INa), the modifications on varying types of ionic currents caused by this drug remain largely unexplored. In pituitary tumor (GH3) cells, we found that the presence of LCS concentration-dependently decreased the amplitude of A-type K+ current (IK(A)) elicited in response to membrane depolarization. The IK(A) amplitude in these cells was sensitive to attenuation by the application of 4-aminopyridine, 4-aminopyridine-3-methanol, or capsaicin but not by that of tetraethylammonium chloride. The effective IC50 value required for its reduction in peak or sustained IK(A) was calculated to be 102 or 42 µM, respectively, while the value of the dissociation constant (KD) estimated from the slow component in IK(A) inactivation at varying LCS concentrations was 52 µM. By use of two-step voltage protocol, the presence of this drug resulted in a rightward shift in the steady-state inactivation curve of IK(A) as well as in a slowing in the recovery time course of the current block; however, no change in the gating charge of the inactivation curve was detected in its presence. Moreover, the LCS addition led to an attenuation in the degree of voltage-dependent hysteresis for IK(A) elicitation by long-duration triangular ramp voltage commands. Likewise, the IK(A) identified in mouse mHippoE-14 neurons was also sensitive to block by LCS, coincident with an elevation in the current inactivation rate. Collectively, apart from its canonical action on INa inhibition, LCS was effective at altering the amplitude, gating, and hysteresis of IK(A) in excitable cells. The modulatory actions on IK(A), caused by LCS, could interfere with the functional activities of electrically excitable cells (e.g., pituitary tumor cells or hippocampal neurons).

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence for Inhibitory Perturbations on the Amplitude, Gating, and Hysteresis of A-Type Potassium Current, Produced by Lacosamide, a Functionalized Amino Acid with Anticonvulsant Properties

Cho

Chuang

2022

IJMS

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“…Among factors influencing the pharmacologic response, individual pharmacokinetic characteristics can be responsible for the lack of therapeutic efficacy. Interindividual Pharmaceuticals 2022, 15, 105 2 of 14 differences in drug metabolism (e.g., extensive versus poor metabolizers) and drug-drug interactions are issues that need to be considered [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

A 5-Year Study of Lithium and Valproic Acid Drug Monitoring in Patients with Bipolar Disorders in an Italian Clinical Center

et al. 2022

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Therapeutic drug monitoring (TDM) is an effective tool used to improve the pharmacological treatment in clinical practice, especially to detect subtherapeutic drug plasma concentration (Cp) in order to consider a change of dosage during treatment and reach its putative therapeutic range. In this study, we report the Cp values of lithium and valproic acid (VPA), alone and in combination, mostly in bipolar patients admitted to an Italian clinical center of the University of Pisa during the years 2016–2020, which include 12,294 samples of VPA, 7449 of lithium and 1118 of both in combination. Lithium and VPA are the most utilized drugs in treating bipolar disorders, and their TDM is strongly recommended by recent guidelines. In relation to lithium Cp monitoring, several studies have underlined that 0.5–0.8 mmol/L is the optimal range for chronic treatment, and below 0.4 mmol/L, it is unlikely to produce a clinical response. For VPA, the therapeutic range is 50–100 μg/mL and a linear correlation between Cp and clinical efficacy has been proposed, where below 50 μg/mL, the clinical efficacy of VPA has not been proven thus far. Toxic levels of both drugs were rarely found in our study, while a high percentage of patients, about one-third, had sub-therapeutic Cp during their treatments. In addition, in several cases of patients receiving multiple blood sampling, the initial subtherapeutic Cp changed only partially without reaching its therapeutic window. In relation to age, we found a higher percentage of lithium and VPA Cp values in range in the adolescents than in the adults and elderly groups. No differences were reported when analyzing the distribution of Cp values in males and females. In conclusion, this present study suggests that TDM is widely used by many specialists, but there is still a window of improvement for optimizing pharmacological treatments in clinical practice.

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“…Pharmacotherapy targeting voltage-gated sodium channels (VGSCs) has been used with some success for the treatment of neuropathic pain (Dib-Hajj et al, 2009;Theile and Cummins, 2011;McKerrall and Sutherlin, 2018;Dib-Hajj and Waxman, 2019;Alsaloum et al, 2020). The anticonvulsant lacosamide (R-2-acetamido-N-benzyl-3methoxypropionamide), which is FDA-approved for the treatment of epilepsy, has been investigated as a potential treatment for diabetic neuropathic pain (Shaibani et al, 2009;Wymer et al, 2009;Ziegler et al, 2010), refractory pain (McCleane et al, 2003), and recently, Na V 1.7-related painful small fiber neuropathy (de Greef et al, 2019), among others (Carona et al, 2021). The clinical effects of lacosamide are thought to be due to its function as a sodium channel blocker (Errington et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Lacosamide Inhibition of NaV1.7 Channels Depends on its Interaction With the Voltage Sensor Domain and the Channel Pore

et al. 2021

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Lacosamide, developed as an anti-epileptic drug, has been used for the treatment of pain. Unlike typical anticonvulsants and local anesthetics which enhance fast-inactivation and bind within the pore of sodium channels, lacosamide enhances slow-inactivation of these channels, suggesting different binding mechanisms and mode of action. It has been reported that lacosamide’s effect on NaV1.5 is sensitive to a mutation in the local anesthetic binding site, and that it binds with slow kinetics to the fast-inactivated state of NaV1.7. We recently showed that the NaV1.7-W1538R mutation in the voltage-sensing domain 4 completely abolishes NaV1.7 inhibition by clinically-achievable concentration of lacosamide. Our molecular docking analysis suggests a role for W1538 and pore residues as high affinity binding sites for lacosamide. Aryl sulfonamide sodium channel blockers are also sensitive to substitutions of the W1538 residue but not of pore residues. To elucidate the mechanism by which lacosamide exerts its effects, we used voltage-clamp recordings and show that lacosamide requires an intact local anesthetic binding site to inhibit NaV1.7 channels. Additionally, the W1538R mutation does not abrogate local anesthetic lidocaine-induced blockade. We also show that the naturally occurring arginine in NaV1.3 (NaV1.3-R1560), which corresponds to NaV1.7-W1538R, is not sufficient to explain the resistance of NaV1.3 to clinically-relevant concentrations of lacosamide. However, the NaV1.7-W1538R mutation conferred sensitivity to the NaV1.3-selective aryl-sulfonamide blocker ICA-121431. Together, the W1538 residue and an intact local anesthetic site are required for lacosamide’s block of NaV1.7 at a clinically-achievable concentration. Moreover, the contribution of W1538 to lacosamide inhibitory effects appears to be isoform-specific.

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Pharmacology of lacosamide: From its molecular mechanisms and pharmacokinetics to future therapeutic applications

Cited by 20 publications

References 87 publications

Evidence for Inhibitory Perturbations on the Amplitude, Gating, and Hysteresis of A-Type Potassium Current, Produced by Lacosamide, a Functionalized Amino Acid with Anticonvulsant Properties

Evidence for Inhibitory Perturbations on the Amplitude, Gating, and Hysteresis of A-Type Potassium Current, Produced by Lacosamide, a Functionalized Amino Acid with Anticonvulsant Properties

A 5-Year Study of Lithium and Valproic Acid Drug Monitoring in Patients with Bipolar Disorders in an Italian Clinical Center

Lacosamide Inhibition of NaV1.7 Channels Depends on its Interaction With the Voltage Sensor Domain and the Channel Pore

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