Impact of pain in other body regions on the foot-specific quality of life in patients with hallux valgus.

OBJECTIVES: The purpose of this study was to clarify the prevalence of pain outside the foot, and to determine the associations of pain outside the foot with foot-specific quality of life (QOL) in patients with hallux valgus. METHODS: Patients scheduled to undergo hallux valgus surgery were recruited. Patients answered whether they experienced disabling pain in 13 body regions other than the foot. Foot-specific QOLwas assessed using the Self-Administered Foot Evaluation questionnaire (SAFE-Q). Foot pain was quantified using the visual analogue scale (VAS). Patient characteristics, including age, sex, comorbidity, anxiety, and depression, were also surveyed. The association between pain elsewhere and the SAFE-Q and pain VAS scores were assessed using univariate and multivariate analyses. RESULTS: Of 102 patients, 55 (54%) experienced pain other than the foot. All SAFE-Q subscale scores were lower, and pain VAS was higher in patients with pain elsewhere than in patients without. In the multivariate analysis, an increase in the number of pain regions was independently associated with a decrease in SAFE-Q scores and an increase in pain VAS. CONCLUSION: More than half of the patients with hallux valgus experienced pain elsewhere. The presence of pain elsewhere was associated with poorer foot-specific QOL and severer foot pain.

Design and synthesis of pyrido[2,3-d]pyrimidine derivatives for a novel PAC1 receptor antagonist.

Since PA-8 (5-(4-(Allyloxy)-3-methoxyphenyl)-2-amino-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione) was recently identified as a novel small-molecule antagonist of the pituitary adenylate cyclase-activating polypeptide (PACAP) type I (PAC1) receptor, a series of pyrido[2,3-d]pyrimidine derivatives have been designed, synthesized and subsequently evaluated for antagonistic activity on the PAC1 receptor. In this study, we synthesized 21 derivatives based on the PA-8 structure. Among them, the compound 2o (2-Amino-5-(3-trifluoromethoxy-phenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione) showed more potent antagonistic activities than PA-8. Intrathecal (i.t.) injection of 2o blocked the induction of PACAP-induced aversive behaviors and mechanical allodynia in mice, and the effects were more potent than those of PA-8. A single i.t. injection of 2o also inhibited spinal nerve ligation (SNL)-induced mechanical allodynia. Repeated intraperitoneal administration of 2o gradually reduced the SNL-induced mechanical allodynia, and this effect appeared earlier than for PA-8. In addition, 2o exhibited a favorable ADME and pharmacokinetics profiles. These results suggest that 2o may become an analgesic for the treatment of neuropathic pain.

Fosphenytoin Alleviates Herpes Simplex Virus Infection-Induced Provoked and Spontaneous Pain-Like Behaviors in Mice.

In this study, we investigated the effects of fosphenytoin (fPHT), a water-soluble prodrug of phenytoin, on the pain responses of a mouse herpes zoster (HZ) pain model. Transdermal herpes simplex virus type 1 (HSV-1) inoculation induced mechanical allodynia and hyperalgesia of the hind paw and spontaneous pain-like behaviors, such as licking the affected skin. Intravenous injection of fPHT (15 and 30 mg/kg) alleviated HSV-1-induced provoked pain (allodynia and hyperalgesia). The suppressive effects of fPHT on provoked pain were weaker than those of diclofenac and pregabalin which were used as positive controls. fPHT, diclofenac, and pregabalin significantly suppressed HSV-1-induced spontaneous pain-like behaviors. Among them, high-dose fPHT (30 mg/kg) showed the strongest suppression. Intravenous fPHT may become a viable option for an acute HZ pain, especially for spontaneous pain.

In Silico Screening Identified Novel Small-molecule Antagonists of PAC1 Receptor.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are present in the spinal dorsal horn and dorsal root ganglia, suggesting an important role of PACAP signaling systems in the modulation of spinal nociceptive transmission. Previously, we found that intrathecal injection of PACAP or maxadilan, a selective PACAP type I (PAC1) receptor agonist, induced transient aversive responses followed by a long-lasting mechanical allodynia in mice, suggesting that PACAP-PAC1 receptor systems are involved in chronic pain and that selective PAC1 antagonists may become a new class of analgesics. Although several PAC1 antagonists, such as PACAP 6-38, have been reported, all of them are peptide compounds. In the present study, we identified new small-molecule antagonists of the PAC1 receptor using in silico screening and in vitro/vivo pharmacological assays. The identified small-molecule compounds, named PA-8 and PA-9, dose dependently inhibited the phosphorylation of CREB induced by PACAP in PAC1-, but not VPAC1- or VPAC2-receptor-expressing CHO cells. PA-8 and PA-9 also dose dependently inhibited PACAP-induced cAMP elevation with an IC50 of 2.0 and 5.6 nM, respectively. In vivo pharmacological assays showed that intrathecal injection of these compounds blocked the induction of PACAP-induced aversive responses and mechanical allodynia in mice. In contrast, the compounds when administered alone exerted neither agonistic nor algesic actions in the in vitro/vivo assays. The compounds identified in the present study are new and the first small-molecule antagonists of the PAC1 receptor; they may become seed compounds for developing novel analgesics.

Spontaneous recurrent hemarthrosis of the knee in the elderly: arthroscopic treatment and etiology.

PURPOSE: To elucidate the etiology of and find a preferable surgical treatment for spontaneous recurrent hemarthrosis in osteoarthritic knee joints arthroscopically. METHODS: Nineteen patients referred to our institution from affiliate hospitals between April 1998 and October 2006 were involved in this study. Their demographics, preoperative radiographic findings, preoperative magnetic resonance imaging (MRI) findings, arthroscopic findings and procedures performed, the patient's medical history, and the postoperative clinical course were retrospectively reviewed. RESULTS: There were 9 male and 10 female patients with average age of 61.9 years (range, 41 to 83 yrs). The average number of joint aspirations before surgery was 5.4. The average time from onset to arthroscopy was 10 months. Radiographs showed 2 knees with isolated lateral compartment osteoarthritis (OA), one with isolated patellofemoral (PF) OA, 14 with medial and lateral compartment OA, and 2 with tricompartmental OA. Classifying them according to the dominant compartment, 6 knees were medial-dominant OA, 11 lateral-dominant OA, and 2 PF-dominant OA. The MRI scans revealed 18 grade III lateral menisci and 1 grade II lateral menisci. Even with 6 medial-dominant OAs, lateral meniscal involvement was more obvious than medial meniscal involvement on MRI. Subtotal lateral meniscectomy accompanied with coagulation of the bleeding points was performed on 17 cases. For 2 PF OA cases, synovectomy and a histologic examination of synovium were performed. Remission was obtained for 18 cases. The unsuccessful case had cirrhosis of the liver. CONCLUSIONS: A majority of the patients (17 of 19) had degenerative torn lateral menisci confirmed with MRI and at arthroscopy. Successful outcomes were achieved by meniscectomy and coagulation. Most so-called spontaneous recurrent hemarthroses in OA knee joints appear to be attributable to torn lateral menisci. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Sarcoidosis presenting as prepatellar bursitis.

A 61-year-old woman complained of a subcutaneous mass in her right knee. MR images revealed a well-defined subcutaneous mass in the prepatellar region, containing some fluid and foci of short T2. The lesion showed some marginal contrast uptake after an administration of meglumine gadopentetate (Gd-DTPA), consistent with prepatellar bursitis. The pathological specimen, however, revealed subcutaneous sarcoidosis involving the bursa.