Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin.

1. Capsazepine is a synthetic analogue of the sensory neurone excitotoxin, capsaicin. The present study shows the capsazepine acts as a competitive antagonist of capsaicin. 2. Capsazepine (10 microM) reversibly reduced or abolished the current response to capsaicin (500 nM) of voltage-clamped dorsal root ganglion (DRG) neurones from rats. In contrast, the responses to 50 microM gamma-aminobutyric acid (GABA) and 5 microM adenosine 5'-triphosphate (ATP) were unaffected. 3. The effects of capsazepine were examined quantitatively with radioactive ion flux experiments. Capsazepine inhibited the capsaicin (500 nM)-induced 45Ca2+ uptake in cultures of rat DRG neurones with an IC50 of 420 +/- 46 nM (mean +/- s.e.mean, n = 6). The 45Ca2+ uptake evoked by resiniferatoxin (RTX), a potent capsaicin-like agonist was also inhibited. (Log concentration)-effect curves for RTX (0.3 nM-1 microM) were shifted in a competitive manner by capsazepine. The Schild plot of the data had a slope of 1.08 +/- 0.15 (s.e.) and gave an apparent Kd estimate for capsazepine of 220 nM (95% confidence limits, 57-400 nM). 4. Capsazepine also inhibited the capsaicin- and RTX-evoked efflux of 86Rb+ from cultured DRG neurones. The inhibition appeared to be competitive and Schild plots yielded apparent Kd estimates of 148 nM (95% confidence limits, 30-332 nM) with capsaicin as the agonist and 107 nM (95% confidence limits, 49-162 nM) with RTX as agonist. 5. A similar competitive inhibition by capsazepine was seen for capsaicin-induced [14C]-guanidinium efflux from segments of adult rat vagus nerves (apparent Kd = 690 nM; 95% confidence limits, 63 nM-1.45 microM).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cervical Anterior Spinal Cord Infarction

Spinal cord infarction or ischemia predominates in the thoracic region, less so in the cervical and lumbar regions. Different etiological factors have been implicated in anterior spinal artery syndrome. Magnetic resonance imaging (MRI) allows in vivo imaging of spinal cord disease, including infarction. A 31-yearold, previously healthy man had an acute onset of interscapular pain, followed by rapid development of quadriparesis associated with paresthesias and mild bladder dysfunction. Initial MRI of the cervicothoracic region demonstrated normal findings. A repeat study obtained 6 days later showed marked increase in the cervical cord size, especially at the C6-7 level. On the T2-weighted sagittal series and after gadolinium injection, increased signal in the anterior portions of the cord extending from C-4 to the T2-3 interspace was noted. This was most prominent at the C-6 and C-7 levels. The coronal views revealed abnormal high signal in the region of the anterior horns of the gray matter, a finding that is recognized as an “owl's eyes” pattern. Because the MRI changes of cerebral infarction may succeed a clinical event by hours or days, accurate diagnosis may require delayed or repeated studies. This report suggests that the diagnosis of spinal cord disease requires a similar evaluation.     

Three balanced anesthetic techniques for neuroanesthesia: infusion of thiopental sodium with sufentanil or fentanyl compared with inhalation of isoflurane.

STUDY OBJECTIVE: To compare emergence from anesthesia and the hemodynamic and respiratory depressant effects of thiopental sodium infusion plus sufentanil or fentanyl with those of isoflurane as the primary component of a balanced technique for neuroanesthesia. DESIGN: Randomized, double-blind, prospective study. SETTING: University hospital and its affiliated Veterans Affairs Medical Center. PATIENTS: Thirty patients undergoing elective craniotomy for aneurysm or tumor. INTERVENTIONS: Thiopental with infusion of sufentanil 0.1 microgram/kg/hr, thiopental with infusion of fentanyl 1 microgram/kg/hr, or inhalation of 0.25% to 2% isoflurane as the major component of a balanced anesthesia technique that included nitrous oxide (N2O) and vecuronium (potency ratio of sufentanil to fentanyl, 10:1). MEASUREMENTS AND MAIN RESULTS: Intraoperative stress response (as indicated by intraoperative hypertension) was said to be the percentage of time the patient required administration of an antihypertensive drug, measuring from the first dose of thiopental to discontinuation of N2O at the end of the procedure, excluding any period of induced hypotension. Rapidity of emergence was measured by the number of minutes from discontinuation of N2O to first opening of the eyes on command. Adequacy of spontaneous ventilation was evaluated by determining partial pressure of arterial carbon dioxide 1, 2, and 3 hours after discontinuation of N2O. Extent of vasoactive drug administration for control of intraoperative hypertension (as determined by the clinicians caring for the patients) was described by minutes of vasodilator infusion and milligrams of propranolol or labetalol administered. The frequency of postoperative hypertension was defined as the number of patients in each group who required medication for postoperative hypertension. No significant differences in variables were found for thiopental/sufentanil, thiopental/fentanyl, or isoflurane when these drugs were used with N2O and vecuronium. CONCLUSIONS: Any one of these balanced anesthetic techniques appears appropriate for craniotomy.     

The indications for elective treatment of the neck in cancer of the major salivary glands.

To define the indications for elective neck treatment, the cases of 474 previously untreated patients were reviewed who had locally confined major salivary gland cancers treated between 1939 and 1982. Clinically positive nodes were present in 14% (67 of 474). Overall, clinically occult, pathologically positive nodes occurred in 12% (47 of 407). By univariate analysis, several factors appeared to predict the risk of occult metastases; however, multivariate analysis revealed that only size and grade were significant risk factors. Tumors 4 cm or more in size had a 20% (32 of 164) risk of occult metastases compared with a 4% (nine of 220) risk for smaller tumors (P less than 0.00001). High-grade tumors (regardless of histologic type) had a 49% (29 of 59) risk of occult metastases compared with a 7% (15 of 221) risk for intermediate-grade or low-grade tumors (P less than 0.00001). In view of the low frequency of occult metastases in the entire group, routine elective treatment of the neck is not recommended. High-grade tumors and larger tumors have a high rate of occult neck metastases, and treatment should be considered in this group.     

Factors affecting patency of internal thoracic artery graft: clinical and angiographic study in 1434 symptomatic patients operated between 1982 and 2002.

OBJECTIVE: The purpose is to define factors influencing long-term patency of the internal thoracic artery (ITA) to optimize the operative strategy. METHODS: 1482 left internal thoracic artery (LITA) and 636 right internal thoracic artery (RITA) symptom-directed angiograms were studied in 1434 patients. Data were prospectively collected from patients who had primary coronary artery bypass surgery during the period 1982-2002. The mean age of patients was 59 years; 85% were male. The mean period from operation to re-angiogram was 80 months. LITA was grafted to left anterior descending coronary artery (LAD) in 82% of cases, RITA to right coronary artery (RCA) in 40% and circumflex artery in 35% of cases. Graft failure was defined as > or =80% stenosis. RESULTS: 96.3% of LITA and 88.1% of RITA grafts were patent. No patient variables were significantly associated with graft patency (age, gender, diabetes, hypertension, LVEF, NYHA, AMI). Target coronary artery was associated with patency of both LITA and RITA grafts with maximum patency when grafted to LAD (P = 0.02) RITA had the worst patency to RCA, patency for the left system was identical to LITA. Proximal anastomosis to aorta (free RITA) had significantly better patency when compared with in situ RITA to RCA system (P = 0.005) while similar patency when grafted to left system. ITA diameter and target artery diameter were not associated with graft patency. Recent operations had better RITA patency (P = 0.03). The interval from operation to angiogram was not associated with ITA patency (96% patency for LITA and 88% patency for RITA, remained stable when studied at <1, 1-4, 5-9, 10-14 and >15 years). CONCLUSIONS: Even in a patient cohort that had adverse symptoms, excellent LITA and RITA patency was achieved which almost remained constant through all time intervals studied.     

Corticosteroids for multiple sclerosis: II. Application for disease-modifying effects

Physicians who treat multiple sclerosis (MS) face the challenge of patients exhibiting ongoing disease activity, including exacerbations, loss of functional capabilities, intellectual decline, and radiologic progression, despite being on a disease-modifying agent (DMA). After searching for factors that might at least in part explain these changes—such as nonadherent drug-taking behavior, or the presence of interfer-on-neutralizing antibodies—some providers may ultimately decide to switch the patient to another DMA. In most circumstances, patients likely derive only partial effects from these agents, even in the absence of compromising factors. Thus, a number of factors must be considered in order to intensify the treatment regimen in response to disease progression. In the context of an inadequate treatment response to a DMA, some clinicians will convert the patient to an alternative therapy, and others will instead use a second agent in combination with the first (the so-called platform agent). In the first of this two-part series, we explored the use of anti-inflammatory CS and ACTH to treat MS exacerbations. Although we underscored the limited availability of evidence-based studies to support specific regimens for this purpose, there is an even greater paucity of data to support the routine use of these agents in order to achieve chronic disease-modifying effects in those who continue to deteriorate clinically, radiographically, or both. Without doubt, a number of factors influence the formulation of combination treatment plan for MS. Nevertheless, we will focus on the rationale and practical schemes that can be considered for using corticosteroids (CS) (and perhaps even ACTH) in an attempt to modify various domains of ongoing disease activity.     

Technical Note: A comparison of a novel direct ophthalmoscope, the OptyseTM, to conventional direct ophthalmoscopes

Despite the current popularity of binocular indirect ophthalmoscopy, direct ophthalmoscopes are still commonly used by clinicians for fundus examination. They are considered to be expensive, however, and it has been suggested that this cost can prevent their use by healthcare professionals in developing countries. The Optyse Lens Free Ophthalmoscope is a novel direct ophthalmoscope, without a lens focus system, that allows for comparatively inexpensive manufacture and supply. We compared the clarity of view with the Optyse to that with standard direct ophthalmoscopes, over a sequential cohort of patients with a variety of refractive errors and ocular conditions. The grade of clarity of view with the Optyse Lens Free Ophthalmoscope was less than conventional ophthalmoscopes (Wilcoxon signed rank test, p < 0.0001). This grade of clarity of view was not associated with the ametropia of the ophthalmoscopic observation (Spearman r < or = 0.03, p > or = 0.28) but was with the presence of cataracts (chi2 test, p < 0.0001) with both the Optyse and the conventional ophthalmoscopes. Despite its limitations, the retinal view with Optyse was often within acceptable clinical limits suggesting that this relatively inexpensive ophthalmoscope may have a place when cost prohibits any other type of ophthalmoscope use.     

Calcium antagonists and blood glucose in normal rabbits

The effects of the calcium antagonists verapamil and nifedipine on blood glucose levels, glucose tolerance, insulin secretion during glucose tolerance and hypoglycaemic effect of tolbutamide were studied in normal nondiabetic rabbits. Daily dosage of 40 mg/kg verapamil and 5 mg/kg nifedipine given orally up to 7 days did not affect blood glucose level, glucose tolerance, insulin secretion during glucose tolerance and hypoglycaemic activity of tolbutamide 250 mg/kg p.o.