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Common/useful drugs
Published in Jonathan P Rogers, Cheryl CY Leung, Timothy RJ Nicholson, Pocket Prescriber Psychiatry, 2019
Jonathan P Rogers, Cheryl CY Leung, Timothy RJ Nicholson
Interactions: ↑risk of ↑QTc with amifampridine, amiodarone, amisulpride, apomorphine, clari-/erythromycin, clopamide, (es)citalopram, fluconazole, haloperidol; ↑risk of ↓K+ (↑risk of torsade de pointes) with aminophylline, corticosteroids, bendroflumethiazide, fludrocortisone, furosemide, ↑CNS depressive fx of alcohol, barbiturates, other sedatives; ↑fx of antihypertensives; ↓fx with TCA.
Neuromuscular Junction Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Diana Mnatsakanova, Qin Li Jiang
3,4-Diaminopyridine (3,4-DAP) is a potassium channel inhibitor and enhances acetylcholine release by enhancing calcium entry into the presynaptic nerve terminal. 3,4-DAP produces clinical benefit in the majority of patients with LEMS: Trials of 3,4-DAP in LEMS patients have demonstrated that it is effective in improving muscle strength and CMAP amplitude24–26Typical initial dose is 5 mg 3–4 times a day. Dose can be increased by 5 mg a day to a maximum of 80 mg daily.It is generally well-tolerated. Common side effects are perioral tingling. Caution should be taken in patients who have history of seizure as it may lower seizure threshold.It is not available in the United States, but may be obtained from certain compounding pharmacies or through a pharmaceutical research protocol.Coadministration with a CI may potentiate the effect of 3,4-DAP.Amifampridine phosphate (Firdapse) is the salt form of the 3,4-DAP base; it was approved by FDA in 2018 to treat LEMS in adults. Starting dose is 15–30 mg orally three times a day.27
Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities
Published in Expert Opinion on Investigational Drugs, 2021
Laurent Servais, Giovanni Baranello, Mariacristina Scoto, Aurore Daron, Maryam Oskoui
Amifampridine (marketed as Firdapse) is currently approved for the treatment of Lambert-Eaton myasthenic syndrome, an autoimmune disorder in which antibodies target voltage-gated Ca2+ channels, resulting in a pre-synaptic pathology of NMJs. Amifampridine acts by blocking pre-synaptic K+ channels thus increasing duration of acetylcholine release in the NMJ cleft [50]. Amifampridine has also been successfully used to treat the post-synaptic NMJ disorder muscle-specific kinase myasthenia gravis and thus appears to be effective in treating both pre- and post-synaptic defects. NMJ defects are a key component in the SMA pathology, as demonstrated both in preclinical and in clinical studies [51–53]. A phase 2 randomized cross-over study to evaluate the safety, tolerability, and efficacy of amifampridine in ambulatory SMA3 patients is currently ongoing (NCT03781479). A cross-over study in adult ambulant SMA3 patients using a similar compound, an extended-release formulation of 4-aminopyridine, that blocks voltage-sensitive potassium channels in the central and peripheral nervous system is now completed and results are pending (NCT01645787).
Amifampridine for the treatment of Lambert-Eaton myasthenic syndrome
Published in Expert Review of Clinical Immunology, 2019
4-Aminopyridine (4-AP; fampridine) was initially used in LEMS, but its use was limited by stimulating effects in the central nervous system, because it readily crosses the blood-brain barrier [36]. 4-AP is twice as toxic and more convulsive than amifampridine in laboratory animals after intravenous administration. 4-AP was used for the symptomatic treatment of LEMS in open trials in nine patients who experienced clinical and electrophysiological improvement [27,39]. However, seizures occurred in two patients. The threat of serious CNS side-effects has thus limited the use of 4-AP in LEMS.
Lambert-Eaton myasthenic syndrome (LEMS) in a patient with lung cancer under treatment with pembrolizumab: a case study
Published in Journal of Chemotherapy, 2023
Jun Ho Lee, Sun Kyung Baek, Jae Joon Han, Hong Jun Kim, Yeon-Ah Lee, Dallah Yoo, Chi Hoon Maeng
Consultations with a neurologist and rheumatologist were performed to evaluate the possibility of an unexplained condition causing the patient’s muscle weakness, such as polymyositis. Needle electromyography and nerve conduction study with high-frequency repetitive nerve stimulation (RNS) test using right abductor digiti minimi, flexor carpi ulnaris and orbicularis oculi muscle was performed (Figure 1). The results of the repetitive stimulation were as follows: in the right ulnar nerve, there was a low amplitude compound muscle action potential (CMAP) response of 0.90 mV, with a 28.6% decrement of CMAP amplitude upon 5-Hz repetitive stimulation and 579% increment of CMAP amplitude upon 50-Hz repetitive stimulation. Immediately following the brief exercise, there was a 536% increase in the CMAP amplitude. Post-exercise facilitation and exhaustion were observed after a brief, intense exercise. A panel of autoantibody test was performed to see if there was an autoimmune mechanism. Although the clinical explanation could not be clearly made, antineutrophil cytoplasmic autoantibody (C-ANCA) and anti-double-stranded deoxyribonucleic acid (dsDNA) immunoglobulin M (IgM) were positive. Although the voltage-gated calcium channel (VGCC) autoantibody test for the confirmation of LEMS was not available in our institute, the electrodiagnostic findings were consistent with LEMS. Table 1 summarizes a series of autoantibody tests performed to determine whether LEMS was caused by paraneoplastic syndrome or non-tumor-associated autoimmune disease. Taken together, these findings suggested that LEMS in this patient was autoimmune-mediated. Since other possible underlying causes could not be identified, it was reasonable to assume that the autoimmune-mediated LEMS was induced by pembrolizumab. Accordingly, pembrolizumab was discontinued. However, unfortunately, the response to therapy for LEMS was poor. There was no symptomatic improvement during the initial treatment with 3,4-diaminopyridine (3,4-DAP; amifampridine) 10 mg three times a day. Furthermore, it was not tolerated because it led to frequent diarrhea. High-dose steroid pulse therapy (500 mg intravenous methylprednisolone for three consecutive days) based on the opinion of the rheumatologist elicited only a transient improvement in muscle weakness. Subsequent therapy with pyridostigmine was also ineffective. After a thorough multidisciplinary discussion with a neurologist and rheumatologist, immunosuppression with azathioprine and prednisolone was started. Currently, after 12 months of treatment with azathioprine and prednisolone, performing activities of daily living such as lifting objects, walking, and brushing or washing his hair, independently remains difficult.At best, the muscle power of both upper and lower extremities was grade 4. Eventually, his leg weakness progressed, requiring a wheelchair for mobility. Despite the immunosuppressive treatment, the patient’s performance status gradually deteriorated (ECOG grade 2–3). After discontinuation of pembrolizumab treatment, there was no disease progression for 12 months. However, hilar lymph nodes enlargement confirmed PD on chest CT performed in March 2021.