Pharmacokinetics and safety of 3,4-diaminopyridine base in healthy Japanese volunteers

Ishida, Natsuko; Kobayashi, Erina; Kondo, Yuya; Matsushita, Ryo; Komai, Koichiro

doi:10.5414/cp202133

Cited by 3 publications

(4 citation statements)

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“…The effect peaks at 1.5 h after oral administration, with treatment effects maintained for 3–8 h. Food intake does not significantly alter the pharmacokinetics of 3,4-DAP. 51 The oral dose needs to be approximately three times that given intravenously to achieve the same efficacy. 50 …”

Section: Pharmaokinetic Profile Of Amifampridinesmentioning

confidence: 99%

Amifampridines are the Most Effective Drugs for Treating Lambert-Eaton Myasthenic Syndrome With a Focus on Pediatric Lambert-Eaton Myasthenic Syndrome

2024

J Clin Neurol

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Section: Pharmaokinetic Profile Of Amifampridinesmentioning

confidence: 99%

Amifampridines are the Most Effective Drugs for Treating Lambert-Eaton Myasthenic Syndrome With a Focus on Pediatric Lambert-Eaton Myasthenic Syndrome

2024

J Clin Neurol

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“…However, effective blood levels and toxic blood levels are not known, and the prescription of 3,4‐DAP is dependent on physician experience. Side effects, such as asthma attacks, cardiac arrhythmia, seizures, perioral and digital paresthesia, cramps, diarrhea, and difficulty sleeping have been reported (Bever et al, ; Flet et al, ; Ishida, Kobayashi, Kondo, Matsushita, & Komai, ; Lundh et al, ; Sanders, , ; Weimer & Wong, ; Wirtz et al, ). However, the rate of occurrence of adverse effects and the dose or plasma concentrations associated with these effects are unknown.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and tissue distribution of 3,4‐diaminopyridine in rats

Ishida

Kondo

Chikano

et al. 2019

Biopharm & Drug Disp

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Lambert-Eaton myasthenic syndrome (LEMS) is characterized by muscle weakness, amyotrophy, easy fatigability, and depressed tendon reflexes. 3,4-Diaminopyridine (3,4-DAP) is the recommended therapy for the treatment of LEMS. However, estimations of 3,4-DAP pharmacokinetics in human and animals, such as rats, are rarely reported because 3,4-DAP is an orphan drug for the treatment of a very rare disease (LEMS). In particular, little is known about its tissue distribution. Therefore, the pharmacokinetics of 3,4-DAP were studied, with particular focus on tissue distribution, in rats. After intravenous administration of 3,4-DAP to rats, the half-life of 3,4-DAP was 15.9 ± 3.9 min and the volume of distribution at steady-state was 2.8 ± 0.7 L/kg. The tissue-to-plasma partition coefficient (Kp) was high in the kidney, heart, and muscle.In addition, with increased steady state plasma concentration (Css), a tendency toward increased Kp was found in most tissues. In the muscle, a likely target region of 3,4-DAP in LEMS patients, the Kp was higher than in the plasma. Furthermore, more than 68% of 3,4-DAP was distributed to the muscle as determined by the ratio of 3,4-DAP distribution calculated from the apparent volumes of distribution. Hence, 3,4-DAP may provide for more effective and long-lasting effects.

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“…Patients are typically prescribed 10-to 20-mg oral doses of 3,4-DAP to be taken several times during the day and report peak clinical effects for 3 to 8 h after each dose (17). 3,4-DAP has been reported to have a serum half-life of 1 to 3 h, and pharmacokinetic studies cite peak serum concentrations of 40 to 110 ng/ml after a 20-mg oral dose (18)(19)(20)(21)(22). Similar doses of 3,4-DAP have also been used off-label for a variety of other neuromuscular weakness conditions, including congenital myasthenic syndrome (23)(24)(25)(26)(27)(28), muscle-specific receptor tyrosine kinase myasthenia gravis (29), downbeat nystagmus (30), and multiple sclerosis (31)(32)(33)(34).…”

mentioning

confidence: 99%

“…In addition, we examined the effects of a supratherapeutic concentration of 3,4-DAP (100 μM) to allow direct comparisons with prior studies that used this higher concentration (41,51,53). For the purpose of this report, we define a supratherapeutic concentration as one that is about 100-fold higher (100 μM) than the measured concentration in the serum of patients with LEMS after taking the typical prescribed dose of 3,4-DAP (18)(19)(20)(21)(22).…”

mentioning

confidence: 99%

A high-affinity, partial antagonist effect of 3,4-diaminopyridine mediates action potential broadening and enhancement of transmitter release at NMJs

Ojala

Ginebaugh

et al. 2021

Journal of Biological Chemistry

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3,4-Diaminopyridine (3,4-DAP) increases transmitter release from neuromuscular junctions (NMJs), and low doses of 3,4-DAP (estimated to reach ∼1 μM in serum) are the Food and Drug Administration (FDA)-approved treatment for neuromuscular weakness caused by Lambert–Eaton myasthenic syndrome. Canonically, 3,4-DAP is thought to block voltage-gated potassium (Kv) channels, resulting in prolongation of the presynaptic action potential (AP). However, recent reports have shown that low millimolar concentrations of 3,4-DAP have an off-target agonist effect on the Cav1 subtype (“L-type”) of voltage-gated calcium (Cav) channels and have speculated that this agonist effect might contribute to 3,4-DAP effects on transmitter release at the NMJ. To address 3,4-DAP’s mechanism(s) of action, we first used the patch-clamp electrophysiology to characterize the concentration-dependent block of 3,4-DAP on the predominant presynaptic Kv channel subtypes found at the mammalian NMJ (Kv3.3 and Kv3.4). We identified a previously unreported high-affinity (1–10 μM) partial antagonist effect of 3,4-DAP in addition to the well-known low-affinity (0.1–1 mM) antagonist activity. We also showed that 1.5-μM DAP had no effects on Cav1.2 or Cav2.1 current. Next, we used voltage imaging to show that 1.5- or 100-μM 3,4-DAP broadened the AP waveform in a dose-dependent manner, independent of Cav1 calcium channels. Finally, we demonstrated that 1.5- or 100-μM 3,4-DAP augmented transmitter release in a dose-dependent manner and this effect was also independent of Cav1 channels. From these results, we conclude that low micromolar concentrations of 3,4-DAP act solely on Kv channels to mediate AP broadening and enhance transmitter release at the NMJ.

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Pharmacokinetics and safety of 3,4-diaminopyridine base in healthy Japanese volunteers

Cited by 3 publications

References 0 publications

Amifampridines are the Most Effective Drugs for Treating Lambert-Eaton Myasthenic Syndrome With a Focus on Pediatric Lambert-Eaton Myasthenic Syndrome

Amifampridines are the Most Effective Drugs for Treating Lambert-Eaton Myasthenic Syndrome With a Focus on Pediatric Lambert-Eaton Myasthenic Syndrome

Pharmacokinetics and tissue distribution of 3,4‐diaminopyridine in rats

A high-affinity, partial antagonist effect of 3,4-diaminopyridine mediates action potential broadening and enhancement of transmitter release at NMJs

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