Silicon-Containing GABA Derivatives, Silagaba Compounds, as Orally Effective Agents for Treating Neuropathic Pain without Central-Nervous-System-Related Side Effects

Fukasawa, Hiroshi; Muratake, Hideaki; Ito, Ai; Suzuki, Hideyuki; Amano, Yohei; Nagae, Marina; Sugiyama, Kiyoshi; Shudo, Koichi

doi:10.1021/cn500053d

Cited by 11 publications

(7 citation statements)

References 29 publications

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“…13,14) In our previous work, we evaluated the analgesic action of novel GABA derivatives containing silicon-carbon bonds and pregabalin in the PSL model (so-called Seltzer model) and the SNL model (so-called Chung model). 10,15) In those studies, we found that orally administered pregabalin significantly increased the withdrawal threshold not only on the ipsilateral operated side (anti-allodynic effect), but also on the contralateral nonoperated side. This increase of pain threshold on the contralateral side, which was observed with a delay compared to the ipsilateral side, can be considered as representing hypoalgesic action due to excessive sedative action on the pain-related higher centers after distribution of pregabalin into the brain.…”

Section: Resultsmentioning

confidence: 82%

Transdermal Administration of Aqueous Pregabalin Solution as a Potential Treatment Option for Patients with Neuropathic Pain to Avoid Central Nervous System-Mediated Side Effects

Fukasawa

Muratake

Nagae

et al. 2014

Biological & Pharmaceutical Bulletin

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Pregabalin, (S)-3-isobutyl-γ-aminobutyric acid (GABA), is a widely used adjuvant therapy for patients with neuropathic pain, which is defined as chronic pain caused by lesions or diseases of the somatosensory nervous system. However, dizziness and somnolence (sleepiness) are common dose-limiting side effects, probably due to excessive sedative effects on higher centers of the central nervous system (CNS) which are involved in the anticonvulsant and analgesic actions of pregabalin. We speculated that transdermal delivery would minimize centrally mediated side effects. To test this idea, we evaluated the analgesic effects of pregabalin delivered through the transdermal route in animal models of neuropathic pain. Transdermally administered pregabalin increased the pain thresholds in response to mechanical stimuli in a partial sciatic nerve ligation model in rats and a spinal nerve ligation model in mice, and surprisingly also in normal animals. It is noteworthy that simple transdermal application of an aqueous solution of pregabalin is effective. This could be a useful treatment option to avoid or minimize the CNS-mediated side effects of orally administered pregabalin.Key words neuropathic pain; pregabalin; transdermal administration Neuropathic pain is chronic pain caused by lesion or disease of the somatosensory nervous system. 1-3) It is characterized by allodynia (pain in response to normally innocuous stimuli), hyperalgesia (increased pain evoked by noxious stimuli) and spontaneous pain. Treatment of neuropathic pain remains a clinical challenge, because the pathophysiology of neuropathic pain is complex and the underlying mechanisms remain poorly understood. 4,5) Although chronic neuropathic pain often responds unsatisfactorily to opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), it can be treated effectively with antidepressants and antiepileptics as adjuvant analgesics. 5) The (S)-isomer of 3-isobutyl-γ-aminobutyric acid (GABA), pregabalin, which was identified as an antiepileptic in the early 1990's, is now widely used for treatment of diabetic peripheral neuropathy, postherpetic neuralgia, spinal cord injury nerve pain, fibromyalgia and partial onset seizures. 6-8) Unfortunately, though, central nervous system (CNS)-mediated side effects such as dizziness and somnolence (sleepiness) are common in pregabalin-treated patients and have a significant impact on their quality of life. 9) Therefore, other treatment options that overcome these problems would provide substantial benefits to patients. Topical application through the transdermal route is one possible option to reduce systemic drug exposure and penetration into the brain, and thereby to minimize CNS-mediated side effects. In this study, therefore, we evaluated the analgesic effects of transdermally administered pregabalin in rats and mice. MATERIALS AND METHODSChemicals Pregabalin (free base) used for experiments in rats was obtained from Sequoia Research Products Ltd. (Pangbourne, U.K.). Pregabalin (crystallized free base) used for experim...

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Section: Resultsmentioning

confidence: 82%

Transdermal Administration of Aqueous Pregabalin Solution as a Potential Treatment Option for Patients with Neuropathic Pain to Avoid Central Nervous System-Mediated Side Effects

Fukasawa

Muratake

Nagae

et al. 2014

Biological & Pharmaceutical Bulletin

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“…A preliminary study was conducted to determine the appropriate dose of pregabalin to induce dizziness. Based on previous studies on the use of pregabalin in rats, experiments were conducted using dosages of 50–200 mg/kg/day . These were the same doses used to achieve an analgesic effect against neuropathic pain in previous studies .…”

Section: Methodsmentioning

confidence: 99%

Effect of hangebyakujutsutemmato on pregabalin‐induced dizziness in a rat model of neuropathic pain

Watanabe

Moriyama

Tokumine

et al. 2019

Traditional & Kampo Medicine

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Aim: This study investigated the efficacy of hangebyakujutsutemmato (HBT) in alleviating disturbances of equilibrium using a rat pregabalin model of neuropathic pain with dizziness. Pregabalin is effective for treating neuropathic pain, but some patients cannot tolerate continued treatment owing to dizziness resulting from pregabalin, especially shortly after beginning treatment. HBT is a Japanese kampo medicine that is used to treat dizziness. Methods: Rats with chronic constriction injury of the sciatic nerve (Bennett and Xie model) underwent the beam balance test to evaluate their sense of equilibrium. The animals were divided into four groups, as follows: pregabalin (50 mg/kg) + HBT (1 g/kg; PH), n = 8; pregabalin (50 mg/kg; P), n = 8; HBT (1 g/kg; H), n = 8; and water (N), n = 8. Pregabalin and HBT treatments were initiated 9 days following injury. Results: On postoperative day 10 (POD10), the day after starting drug treatment, there was a significant difference in the crossing time between PH and P (P < 0.01). The crossing time in group P recovered to a level similar to the other groups on POD16. Conclusion: HBT alleviated the disturbance of equilibrium resulting from pregabalin in a rat model of neuropathic pain. This suggests that HBT may also alleviate dizziness and/or accelerate recovery from dizziness due to pregabalin treatment in humans.

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“…Further optimization of the series led to the development of compounds 160 and 161 . In rotarod experiments, rats administered with pregabalin lost their balance, showing CNS side effects.…”

Section: Silicon-containing Amino Acidsmentioning

confidence: 99%

“…158 Marutake et al synthesized and evaluated the silicon analogs of pregabalin (Figure 42). 159,160 Pregabalin is an analog of γaminobutyric acid (GABA), a neurotransmitter present in the central nervous system. It is used to treat epilepsy and neuropathic pain.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds

2017

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In order to optimize a lead molecule for further development, bioisosteric replacements are generally adopted as one of the strategies. Silicon appears to be the right choice as a carbon isostere because of the similarity in chemical properties. Silicon can be strategically introduced in a molecule to modulate its druglike properties, providing medicinal chemists with an unconventional strategy for replacing a carbon atom. Silicon can also be introduced to replace other heteroatoms and can act as a surrogate of functional groups such as olefin and amide as well. The present Perspective focuses on the opportunities that silicon incorporation offers in drug discovery, with an emphasis on case studies where introduction of silicon has created a benefit over its analog. We have tried to highlight all the recent developments in the field and briefly discuss the challenges associated with them.

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Silicon-Containing GABA Derivatives, Silagaba Compounds, as Orally Effective Agents for Treating Neuropathic Pain without Central-Nervous-System-Related Side Effects

Cited by 11 publications

References 29 publications

Transdermal Administration of Aqueous Pregabalin Solution as a Potential Treatment Option for Patients with Neuropathic Pain to Avoid Central Nervous System-Mediated Side Effects

Transdermal Administration of Aqueous Pregabalin Solution as a Potential Treatment Option for Patients with Neuropathic Pain to Avoid Central Nervous System-Mediated Side Effects

Effect of hangebyakujutsutemmato on pregabalin‐induced dizziness in a rat model of neuropathic pain

Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds

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