Quantitation of pyrrole-imidazole polyamide in rat plasma by high-performance liquid chromatography coupled with UV detection.

A simple and robust method using high-performance liquid chromatography with UV detection was developed and validated for the determination of six pyrrole-imidazole (PI) polyamides (HN.49, TGF-ß1f, TGF-ß1t, HN.50f, HN.50t, and LOX-1) in rat plasma. After the plasma proteins were precipitated with methanol containing phenacetin as an internal standard, the analytes were separated on a Luna C18 (2) (5 µm, 4.6 × 150 mm). Calibration curves were linear over the range of 0.5 to 200 µg/mL for HN.49, 0.25 to 200 µg/mL for TGF-ß1f, TGF-ß1t, HN.50t, and LOX-1, 1 to 200 µg/mL for HN.50f in rat plasma. The inter- and intraday precision were below 15%, and the accuracy was within 15% at the quality controls. The validated method was successfully applied to sample analysis for the pharmacokinetic study.

Synthesis and pharmacological evaluation of 3-amino-1-(5-indanyloxy)-2-propanol derivatives as potent sodium channel blockers for the treatment of stroke.

In investigating potent sodium (Na(+)) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na(+) channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na(+) channels and a significantly low affinity for dopamine D(2) receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na(+) channels, which suggests that 4b would act as a use-dependent Na(+) channel blocker in sustained depolarization during ischemic stroke.

Clinical investigation of patients who develop neuropathic tooth pain after endodontic procedures.

INTRODUCTION: This study aimed to determine the characteristics of patients with neuropathic tooth pain (NTP) who were selected from a group of patients who developed persistent pain after undergoing endodontic procedures. METHODS: Of 271 patients who had chronic persistent pain that did not respond to previous endodontic procedures and were referred to the Endodontic Team of the Nippon Dental University Hospital, 16 patients (5.9%; mean age, 46.8 years; 13 women) who fulfilled the diagnostic criteria for NTP were recruited. The inclusion criteria for the patients were the presence of chronic persistent pain and other pain-related symptoms, despite the absence of major pathology. RESULTS: Pain predominantly occurred in the maxilla (14 patients). In 10 patients (62.5%), NTP developed after retreatment. Daily application of tricyclic antidepressants produced pain relief in 11 patients (68.8%). CONCLUSIONS: These results indicated that NTP is a rare type of chronic intractable endodontic pain and that careful diagnosis of NTP is important.

Pharmacokinetics/pharmacodynamics of acetaminophen analgesia in Japanese patients with chronic pain.

Acetaminophen (APAP) is a popular analgesic. In the present study, we characterized the pharmacokinetics and pharmacodynamics of APAP in the Japanese. Five healthy volunteers were administered 1000 mg of APAP orally. Five patients with chronic pain were administered the optimal oral dose of APAP ranging from 600 to 1000 mg to allow for an adequate analgesic effect. Plasma APAP and APAP metabolite concentrations were measured in the volunteers, plasma APAP concentrations and pain scores using a visual analog scale were measured in the patients with chronic pain. Patient data were fitted to a first-order absorption one-compartment model with delayed effects accounted for by an effect compartment. A sigmoid Emax model was used as the pharmacodynamic model. Acetaminophen-cysteine metabolites, which are conjugates of the toxic metabolite N-acetyl-p-benzoquinone-imine, were detected in the plasma at levels lower than 0.2 microg/ml, but no side effects were observed. The pharmacokinetic and pharmacodynamic parameter (mean+/-S.D.) estimates were as follows: clearance, 18.7+/-4.7 l/h; distribution volume, 30.9+/-6.8 l; absorption rate constant, 2.4+/-1.3 h(-1); rate constant for the elimination of APAP from the effect compartment, 1.3+/-0.5 h(-1); maximum pain relief score, 4.6+/-2.2 units; effect compartment concentration at 50% maximum, 2.0+/-1.2 microg/ml; and sigmoid factor, 1.3+/-0.7. These results suggest that these parameters can be used to determine an effective APAP dosage regimen for Japanese patients with chronic pain.

Efficacy of 1% ropivacaine at sacral segments in lumbar epidural anesthesia.

BACKGROUND AND OBJECTIVES: It is suggested that the potency of 1% ropivacaine is comparable to that of 0.75% bupivacaine and higher than that of 2% lidocaine. Alkalinized lidocaine reportedly enhances the block of sacral segments during lumbar epidural anesthesia. We hypothesized that 1% ropivacaine might also block at the lumbosacral segments adequately during lumbar epidural anesthesia. METHODS: Forty-two patients undergoing lumbar epidural anesthesia at L4-5 or L5-S1 were randomly divided into 3 groups and received either 14 mL 2% lidocaine (lidocaine group), 2% lidocaine with epinephrine 1:200,000 and bicarbonate (lidocaine-epinephrine-bicarbonate group), or 1% ropivacaine (ropivacaine group). Pain threshold after repeated electrical stimulation was used to assess sensory block at the L2, S1, and S3 segments while motor block was evaluated using the modified Bromage Scale. RESULTS: Demographic data were comparable between the groups. Significant differences in the pH of each local anesthetic solution were found between the 3 groups. Pain thresholds at the S1 and S3 segments in the lidocaine-epinephrine-bicarbonate group were significantly higher and sensory block onset faster than in the other groups. However, no significant differences were found in either the pain threshold or the onset of sensory block of the L2 segment between the groups. No significant differences in the pain threshold, onset of sensory block, or Bromage Scale were found between the lidocaine and ropivacaine groups. CONCLUSIONS: We conclude that 1% ropivacaine does not improve block of sacral segments within 20 minutes following epidural ropivacaine administration.

Epidural bolus injection with alkalinized lidocaine improves blockade of the first sacral segment--a brief report.

PURPOSE: It has been reported that the addition of epinephrine and/or bicarbonate to local anesthetic enhances the depth of epidural blockade and that initial partial bolus injection results in greater caudal spread. We evaluated the anesthetic effects of lidocaine with epinephrine and/or bicarbonate injected into the epidural space by bolus or catheter injection. METHODS: Forty-four patients undergoing epidural anesthesia with 17 mL of 2% lidocaine containing 1:200,000 epinephrine at L4-5 or L5-S1 were randomly divided into four groups. Lidocaine was administrated via epidural catheter [lidocaine catheter (LC) group] or Tuohy needle (lidocaine bolus group), lidocaine-bicarbonate was administrated via catheter (lidocaine-bicarbonate catheter group) or needle [lidocaine-bicarbonate bolus (LBB) group]. Pain threshold after repeated electrical stimulation was performed at L2 and S1 regions. Motor blockade was evaluated using the Bromage scale. Sympathetic blockade was assessed with plethysmographic waveforms from the toe. RESULTS: The pain threshold of the S1 dermatome in LBB group was significantly higher than in the lidocaine only groups, however, differences in the pain threshold at the L2 dermatome among the groups were insignificant. The onset of sensory blockade in the S1 dermatome in the LBB group was significantly shorter than in the LC group. Significantly greater motor blockade was achieved in the lidocaine-bicarbonate groups than in the lidocaine-only groups. The amplitude of plethysmographic waveforms significantly increased within each group. CONCLUSION: Epidural bolus injection of lidocaine-bicarbonate with epinephrine improves the pain threshold and speeds the onset of the blockade of the first sacral region.