Junko Ajimi

Effect of three peptidase inhibitors on antinociceptive potential and toxicity with intracerebroventricular administration of dynorphin A (1–17) or (1–13) in the rat

AbstractPurposeThe N- and C-terminal regions of dynorphin (Dyn) A (1–17) activate opioid and N-methyl-D-aspartate receptors, respectively. Earlier studies demonstrated that Dyn-converting enzyme cleaved Dyn A (1–17) mainly at the Arg6–Arg7 bond, resulting in the production of N- and C-terminal region peptide fragments, and that this enzyme was not inhibited by a mixture of the three peptidase inhibitors (PIs) amastatin (A), captopril (C), and phosphoramidon (P). The purpose of the present study was to evaluate antinociceptive potential and toxicity with intracerebroventricular administration of Dyn A (1–17) or (1–13) under pretreatment with a mixture of A, C, and P and/or Dyn-converting enzyme inhibitor (p-hydroxymercuribenzoate).MethodsPeptide fragments from Dyn A (1–17) following incubation with membrane preparation under pretreatment with a mixture of the three PIs was identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI–TOF–MS). Infusion of drugs and peptides into the third ventricle in rats was performed via indwelling cannulae. Induction of antinociception and toxicity by Dyn A (1–17), Dyn A (1–13), Dyn A (1–6), or Dyn A (7–17) were determined by the tail-flick test and induction of barrel rotation, respectively. The effects of the PIs on antinociception and toxicity were evaluated by a dose−response study and a comparison of differences among various combinations of Dyn A (1–17) or Dyn A (1–13) and the three PIs and p-hydroxymercuribenzoate.ResultsMALDI–TOF–MS analysis identified Dyn A (1–6) and Dyn A (1–10) fragments as products following incubation of Dyn A (1–17) with membrane preparation of rat midbrain under pretreatment with a mixture of the three PIs. Pretreatment with a mixture of the three PIs produced an approximately 30-fold augmentation in antinociception induced by low-dose intracerebroventricular administration of Dyn A (1–17) or (1–13) in a μ-, δ- and κ-opioid receptor antagonist-reversible manner, but without signs of toxicity such as barrel rotation in the rat. Dyn A (1–17)-induced antinociception and toxicity was greater than that of Dyn A (1–6), Dyn A (1–13), or Dyn A (7–17) at the same dose. Dyn A (1–17)-induced antinociception and toxicity under pretreatment with various combinations of the three PIs and p-hydroxymercuribenzoate was greater than that with a mixture of the three PIs alone.ConclusionThese findings suggest that administration of a mixture of the three PIs increases Dyn A (1–17)- or (1–13)-induced antinociception under physiological conditions without toxicity.

Pharmacotherapy for Neuropathic Pain in Japan

Neuropathic pain (NeP) results from injury to, or disease of, the peripheral or central components of the neural systems involved in pain. In contrast to inflammatory pain, NeP can persist after healing from the initial injury has resolved. Antipyretic agents, such as non-steroidal anti-inflammatory drugs, steroids, and acetaminophen are ineffective, while specific agents such as gabapentinoids, antidepressants, antiepileptics, and opioids are effective in treating NeP. In this review, we address the definition of NeP, pharmacotherapy for NeP in Japan, pain classification, setting goals for successful NeP medication, and the Japanese algorithm for the pharmacotherapy of NeP with specific prescription guidance.

Unexpected difficult intubation owing to a tracheal web in a patient with past history of a Fontan procedure

To the Editor: Acquired tracheal web is a rare late complication of tracheal intubation and is formed during the development of a laryngeal granuloma [1]. We report an unexpected case of tracheal web encountered after induction of general anesthesia. A 24-year-old male patient (height 168 cm, body weight 52 kg) with acute cholecystitis was scheduled to undergo laparoscopic cholecystectomy. His medical history included transposition of the great arteries, modified Fontan surgery at 6 years of age, and Fontan surgery at 23 years of age, in which he had had postoperative intubation with an 8.5-mm internal diameter (ID) tube for less than 24 h. He had no respiratory symptoms. His physical status was American Society of Anesthesiologists (ASA) performance status (PS) III. After anesthesia was induced and muscle relaxation was achieved, tracheal intubation was attempted. The Cormack grade of the glottic view was I and a subglottic tracheal web was observed (Fig. 1a). Because tracheal intubation with 8.0-, 7.5-, and 7.0-mm ID tubes was impossible owing to resistance, the cholecystectomy was cancelled. The tracheal intubation was needed for transesophageal echocardiography (TEE) monitoring, in the event of acute heart failure caused by pneumoperitoneum—a risk for patients with a history of Fontan procedure. Otolaryngologists examined the larynx using a flexible fiberscope, and laryngomicrosurgery was planned for the following day. Under anesthesia, tracheal intubation was performed with a 6.0-mm ID tube inserted above the web, using a tracheal tube introducer (15 Fr, Portex, Kent, UK). The tracheal web was visualized using a direct laryngoscope (Fig. 1b) and was removed using microscissors. Postoperatively, beclomethasone inhalation was administered and no glottal swelling was found. Fibrotic tissue was found on pathological examination. The cholecystectomy was performed 6 days after the laryngomicrosurgery. Under anesthesia, an 8.0-mm ID tube was inserted without resistance. A FloTrac sensor and PreSep central venous catheter (Edwards Lifesciences, Irvine, CA, USA) were used for circulatory management in the event of acute heart failure and TEE was used for cardiac monitoring. Instead of laparoscopic surgery, open surgery was performed, owing to adhesions. Vital signs remained stable during the operation and postoperative tracheal tube extubation was uneventful. Tracheal webs are late and rare sequelae of tracheal intubation and tracheotomy. Neck extension, and the prone and lateral positions, a larger tracheal tube, and a prolonged intubation period tend to increase the incidence of tracheal webs [1]. The mean duration of tracheal intubation was 5.2 days in patients with a laryngeal granuloma at the cuff site [1], and there is one report of a tracheal web in a patient under mechanical ventilation for a month [2]. While many patients with tracheal web have asthma or chronic obstructive pulmonary disease [3] others have no respiratory symptoms [2]. According to the algorithm for management, the first choice for patients without respiratory symptoms is conservative treatment, and for patients J. Ajimi (&) J. Nishiyama A. Ando T. Suzuki Department of Anesthesiology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan e-mail: ajimi@is.icc.u-tokai.ac.jp