Micromolar lidocaine selectively blocks propagating ectopic impulses at a distance from their site of origin

Abnormal impulses caused by very slowly inactivating Na channels of peripheral nerve have been proposed to play a critical role in neuropathic pain. Low concentrations of local anesthetics, often effective in treating experimental and clinical neuropathic pain, are also known to potently suppress the long after-depolarizations induced by these persistently open Na channels. However, these drug actions on impulses that have propagated away from such sites are undetermined. In the present study, the focal application of anemone toxin II (ATX, 300 nM), which slows Na-channel inactivation, produced prolonged depolarizing after-potentials and, coincidentally, induced spontaneous bursting impulse activity that propagated away from the site of ATX application in the frog sciatic nerve in vitro. The application of low concentrations of lidocaine (1-10 microM), both at the site of ATX exposure and at a distant site, selectively and reversibly inhibited the spontaneous bursting, while having no effect on the electrically stimulated initial spike of the compound action potential. Inhibition occurred as a shortening of burst episodes rather than a reduction in frequency of impulses within a burst or a reduction of intraburst impulse amplitude. Tetrodotoxin also inhibited the induced spontaneous activity, but only at concentrations that also depressed the compound action potential spike. These findings show that low concentrations of lidocaine can restore normal firing patterns in nerve where hyperexcitability has been caused by delayed Na-channel inactivation, without acting directly at the site where ectopic impulses are generated. Thus, it appears that the pattern of abnormal activity rather than an abnormally gating Na channel per se can be a target for lidocaine's therapeutic action.     

Hydrophobic and ionic factors in the binding of local anesthetics to the major variant of human alpha1-acid glycoprotein

Understanding the interaction of local anesthetics (LAs) with plasma proteins is essential to understanding their systemic pharmacology and toxicology. The molecular determinants of LA binding to the major variant (F1*S) of human alpha1-acid glycoprotein (AGP) were therefore investigated spectrofluorometrically using whole AGP and a novel, F1*S variant-selective probe previously developed in our laboratory. Equilibrium- competitive displacement of this probe by LAs, observed by the recovery of AGP's fluorescence as the quenching probe was displaced from its high-affinity site, was characterized by inhibitory dissociation constants for the various LAs. The importance of electrostatic factors was assessed by examining the pH dependent binding of an ionizable LA, lidocaine, using the quaternary lidocaine derivative QX-314 [N-(2,6-dimethylphenylcarbamoylmethyl) triethylammonium chloride] to control for pH dependent ionization of AGP. Uncharged lidocaine bound with at least 8 times the affinity of protonated lidocaine (K(D) = 4.0 +/- 0.6 microM and >32 microM, respectively). This result is inconsistent with the current model of the AGP-binding site, which depicts a buried pocket having a negatively charged region that interacts with the amino termini of basic drugs. Consistent with the model, however, two sets of structurally homologous LAs (mepivacaine, ropivacaine, bupivacaine, and lidocaine, RAD-240, RAD-241, RAD-242, L-30, W-6603) demonstrated a strong positive correlation between hydrophobicity (measured as the octanol:buffer partition coefficient of the neutral species) and their free energies of dissociation. Given that the tertiary structure of AGP has proven refractory to resolution, these structure-activity studies should contribute to understanding the nature of the binding site on this important protein.     

Meniscal injuries: detection using MR imaging

Both retrospective and blinded analyses of thin-section, high-resolution magnetic resonance (MR) images of the knee joint, produced using a solenoid surface coil, indicate that MR imaging is an effective technique for evaluating meniscal injuries. Images of 49 patients were evaluated, and the results were correlated with those of subsequent arthroscopy. A grading scale was developed to rate the index of suspicion of a meniscal tear based on the MR images. Overall, approximately 80% of menisci rated grade 4 (definite tear) or 3 (probable tear) were found to have corresponding tears at arthroscopy. In many other patients with a grade 4 or 3 meniscus in whom a corresponding tear was not found arthroscopically, meniscal tears at other sites or other abnormalities were correctly diagnosed using MR. A majority of the false-positive MR images involved the posterior horns of the menisci, the sites of most false-negative arthroscopic diagnoses. The predictive value of a negative MR image was almost 100%. Even in patients with moderate-to-large effusions, the menisci were accurately evaluated. The results imply that MR imaging is useful in the preoperative evaluation of suspected meniscal tears.     

Reduction of Postincisional Allodynia by Subcutaneous Bupivacaine: Findings with a New Model in the Hairy Skin of the Rat

Background: An incision of hairy skin of the rat's back provides a new model for postincisional pain to determine the importance of cutaneous anesthesia.

Methods: Male Sprague-Dawley rats were anesthetized with sevoflurane and given a 0.6-ml subcutaneous injection of bupi-vacaine (0.25%) under the incision site or the medial lumbar dorsum or at the nuchal midline, 30 min before a 1.0-cm skin incision. Mechanical stimuli (von Frey hairs, 18-250 mN) were applied to measure nociception, indicated by twitching of local subcutaneous muscles, the cutaneus trunci muscle reflex. A graded response score, averaging the twitches weighted by their vigor, or a population response score, measuring the fraction of rats that showed any response, was assessed for 3 days before and over 7 days after incision. von Frey hairs were applied 0.5 cm from the incision to test primary hyperalgesia and 2.0 cm contralateral to the incision for secondary hyperalgesia.

Results: Incision induced responses to stimuli that had no effect on intact skin (allodynia) and also enhanced responses to forces that normally gave less than the full reflex (hyperalgesia). Hyperalgesia was present 30 min after surgery, peaked at 3-6 h, and persisted through the week; allodynia had a similar onset but was briefer. Both changes were transiently reversed by subcutaneous morphine (2.5 mg/kg intraperitoneal). Subcutaneous bupivacaine (0.25%), injected preoperatively at the incision site and anesthetizing skin for 2-3 h, suppressed primary allodynia for 1 week but had no effect on hyperalgesia. Secondary allodynia was obliterated, and secondary hyperalgesia attenuated by this treatment. Bupivacaine injected subcutaneously at the nuchal midline before surgery was also effective in abbreviating primary and secondary allodynia, with no signs of sedation, ataxia, or preconvulsive behavior.     

Percutaneous drainage access: a simplified coaxial technique

We describe an access technique that we have used in 150 nephrostomy and biliary drainage procedures and for access to some abscesses and viscera. The system provides safe coaxial access with a 22-gauge removable hub needle, which then acts as a guide wire and is replaced by an 18-gauge cannula. A major advantage is that only one guide wire is used (0.038-inch) for the entire drainage procedure. No significant complications have occurred to date with this method.     

Interventional radiology in the spleen

Despite the widespread use of interventional radiologic techniques, there has been reluctance to apply these to the spleen. Concern for bleeding and difficulty in negotiating around the colon and pleura have limited its use. The authors report their experience with interventional radiology of the spleen in 35 cases, including percutaneous biopsy (n = 5), diagnostic and therapeutic fluid aspiration (n = 14), and catheter drainage of abscesses (n = 9), hematomas (n = 2), intrasplenic pancreatic pseudocysts (n = 2), and necrotic tumor (n = 1). Transsplenic fluid aspiration and biopsy of the pancreas and adrenal gland were performed as well (n = 2). All procedures were performed under computed tomographic or ultrasound guidance. Biopsies were performed with 22- or 20-gauge needles only; no complications were encountered. Diagnoses included primary and secondary malignancies and an infectious process. Drainages were successful in 11 of 14 patients; pleural effusions occurred in two cases, but neither required specific therapy. Interventional radiologic procedures in the spleen are feasible, and the authors discuss methods to promote their safe application.     

Differential efficacy of intravenous lidocaine in alleviating ipsilateral versus contralateral neuropathic pain in the rat

In the this study we have investigated the threshold plasma concentration of lidocaine for reversal of mechanical ‘allodynia' in a neuropathic pain model in the rat, defined the concentration-dependent limits of that reversal and compared the acute reversal during intravenous drug infusion with the persistent relief of allodynia assayed 48 h later. Actions of i.v. lidocaine on ipsilateral and contralateral legs were also assessed. Forty rats were sorted into five groups (n=7–10) and underwent spinal root (L5–6) ligation to produce allodynia, as quantified by a lower force of von Frey hairs at the plantar hindpaw required to elicit paw withdrawal (PWT, paw withdrawal threshold). During surgery, intravenous catheters were placed for programmed lidocaine infusion and in some animals arterial catheters were also inserted for assaying lidocaine blood levels. PWTs were measured in ipsilateral and contralateral paws before and after ligation and during infusions which, beginning at 5 days after surgery, were conducted every other day to incrementing levels (1.1–9.7 μg/ml plasma). Ligation produced allodynia in ipsilateral paws (PWT=1.22±0.42 g (±SEM)) and in contralateral paws (PWT=4.99±0.61 g), both markedly lower than pre-operative control values for either paw (11.31±0.41 g). The ipsilateral allodynia was partially, but significantly and permanently reversed (to PWT=6–8 g) after a lidocaine infusion to 2.1 mg/ml in two separate groups (n=7, 8). Lower concentrations resulted in elevation of PWT during infusion but no sustained relief. The elevation of PWT during infusion at this threshold level among individual animals was positively correlated with the relief measured 48 h later, but higher lidocaine concentrations infused in subsequent dosings could exact no further sustained relief. The residual PWT level, after reversal by threshold lidocaine and greater, was constant for each individual rat tested over the next 14 days but varied substantially among individuals; some were restored to pre-operative PWTs and some were totally unresponsive to drug. Retrospective analysis revealed a significant and unanticipated correlation between the incidence of low pre-operative PWTs (<10 g) and a lack of sustained reversal of post-operative allodynia by lidocaine. Contralateral allodynia, despite its acute reversal during infusion to 2.1 μg/ml and higher, was not persistently relieved after infusion of lidocaine to any concentration. Repeated infusions to subthreshold levels (<2 μg/ml) did not provide persisting relief of allodynia on either side, and infusions of saline were impotent. These findings show that experimental allodynia results from multiple factors, only some of which are sensitive to lidocaine treatment, and that prolonged reversal of allodynia is limited in extent and likely influenced by pre-existing factors.     

Association between palmoplantar pustulosis and cigarette smoking in Brazil: a case–control study

Background  Palmoplantar pustulosis (PPP) discloses some differences compared to vulgar psoriasis (PV) in terms of age of onset, female predominance and low occurrence of psoriasis lesions elsewhere. Cigarette smoking has been associated to PPP in international studies; nevertheless, these studies were never performed among Brazilian.
Objectives  To compare prevalence of smoking among PPP, PV and other dermatologic patients (NPD).
Methods  Case–control study involving 25 PPP patients from a reference psoriasis centre. Two control groups were matched according to gender and age: 50 patients with PV and 50 NPD. Confounders were adjusted by conditional multiple logistic regression.
Results  Among cases, 84.0% were female and PPP age of disease onset (41.4 years) was greater than PV (34.5 years). Prevalence of ever smoking was higher among cases (92.0%) than PV (52.0%) and NPD (30.0%). Adjusted odds ratio of PPP ever smoking compared to PV and NPD was 9.5 and 36.2, respectively. All smokers reported the onset of their habit before the development of PPP.
Conclusions  There was significant association between PPP and smoking. However, the impact of giving it up in the clinical course of the disease remains to be established.     

MR imaging of the scrotum: normal anatomy

High-resolution magnetic resonance (MR) imaging with a surface coil was utilized to evaluate the normal scrotum. Scrotal contents, spermatic canal, and inguinal regions were visualized within the same field of view. Differences in signal intensity in the testis, epididymis, tunica albuginea, fluid, fat, and spermatic cord allowed for clear delineation of these structures in detail. The high contrast and spatial resolution of MR imaging, coupled with the wide field of view and absence of ionizing radiation, make MR imaging well suited for evaluation of the scrotum.