A multicentre open-label safety and efficacy study of tetrodotoxin for cancer pain.

BACKGROUND: Cancer pain is highly prevalent, and existing treatments are often insufficient to provide adequate relief. OBJECTIVES: We assessed the long-term safety and efficacy of subcutaneous tetrodotoxin treatment in reducing the intensity of chronic cancer-related pain. METHODS: In this multicentre open-label longitudinal trial, 30 µg tetrodotoxin was administered subcutaneously twice daily for 4 days in a heterogeneous cohort of patients with persistent pain despite opioids and other analgesics. "Responder" was defined as a mean reduction of 30% or more in pain intensity from baseline; and "clinical responder" as some pain reduction, but less than 30%, plus agreement on the part of both the patient and the physician that a meaningful analgesic response to treatment had occurred. RESULTS: Of 45 patients who entered the longitudinal trial, 41 had sufficient data for analysis. Of all 45 patients, 21 (47%) met the criteria for "responder" [16 patients (36%)] or "clinical responder" [5 patients (11%)]. Onset of pain relief was typically cumulative over days, and after administration ended, the analgesic effect subsided over the course of a few weeks. No evidence of loss of analgesic effect was observed during subsequent treatments (2526 patient-days in total and a maximum of 400 days in 1 patient). One patient withdrew from the study because of adverse events. Toxicity was usually mild (82%) or moderate (13%), and remained so through subsequent treatment cycles, with no evidence of cumulative toxicity or tolerance. CONCLUSIONS: Long-term treatment with tetrodotoxin is associated with acceptable toxicity and, in a substantial minority of patients, resulted in a sustained analgesic effect. Further study of tetrodotoxin for moderate-to-severe cancer pain is warranted.

Receptive fields and properties of a new cluster of mechanoreceptor neurons innervating the mantle region and the branchial cavity of the marine mollusk Aplysia californica.

The rostral LE cluster (rLE) is a new set of mechanoreceptor neurons of the abdominal ganglion innervating the mantle area, the branchial cavity, the gill and the siphon of the marine mollusk Aplysia californica Cooper. We have compared the organization of rLE cell receptive fields with that of three other clusters of sensory neurons in the abdominal ganglion (LE, RE and RF) that we have reanalysed. There is extensive overlap of receptive fields from the four populations of sensory cells, and the most exposed areas of the mantle are the most densely innervated. The sensory threshold is similar for all groups. The action potentials of the LE, rLE and RE neurons are broadened by serotonin and the peptide SCPB and narrowed by dopamine and FMRFamide. The RF group does not show the same kind of sensitivity to these neuromodulators. The synaptic outputs of the LE and rLE neurons undergo similar synaptic depression and homosynaptic and heterosynaptic facilitation. We estimate that 100 mechanoreceptor neurons innervate the entire mantle and siphon skin, gill and branchial cavity of Aplysia. The degree of their convergence onto various interneurons and motor neurons mediating the gill- and siphon-withdrawal reflex and other reflexes is under investigation.

Surface studies of calcium oxalate dihydrate single crystals during dissolution in the presence of urine.

Single crystals of Calcium Oxalate Dihydrate (COD) were grown from solution under controlled release of the reacting ions. Dissolution of COD was studied at different pH levels and in different dilutions of urine. The descriptors of the contour were determined during dissolution of COD using a quantitative morphological technique. The shape parameters and surface ruggedness were determined from Fourier and fractal analysis. The results obtained give quantitative information on the dissolution kinetics and the surface geometry of COD crystals in normal and diluted urine. Dissolution inhibition and morphological changes of COD crystals during dissolution were attributed to selective adsorption of urine non-ionic macromolecules on the crystal stepped surface. Surface etching of COD was found to depend on urine dilution and time of incubation. The data obtained suggest that the geometric structure of the surface is likely to be a potential factor in understanding crystal aggregation in stone formation.

Pulmonary function loss in Vermont granite workers. A long-term follow-up and critical reappraisal.

Previous studies of Vermont granite workers averred that pulmonary function loss was occurring at 2 to 3 times the normal rate. The excess loss was attributed to the current, relatively low concentrations of dust prevailing in the stone sheds. Because the Vermont State Health Department had traditionally provided surveillance of granite workers to detect evidence of occupationally related illness, we offered pulmonary function screening to any currently employed worker. Spirometric data from the first 150 workers, compared with data from the previous studies, showed a large increase in the FVC and a smaller increase in the FEV1. We therefore undertook a survey of the entire stone shed work force, as well as of retired workers tested previously. The results in 487 current workers indicated an overall increase in FVC from 1974 to 1979 of 0.540 L, and an increase in FEV1 of 0.030 L: predicted losses based on the previous studies were 0.350 to 0.400 L in FVC and 0.250 to 0.350 L in the FEV1. Analysis of data in various subgroups, such as retired workers or those with more than 20 yr of work experience, also showed increases in FVC, and either slight gains or minimal losses in FEV1. The possible reasons for apparent improvement in pulmonary function are discussed. We concluded that technical deficiencies in the previous studies led to exaggerated and erroneous estimates of loss. At this time, the actual decrement in pulmonary function values for exposed granite workers is not known and requires further investigation. Because the newly proposed, stricter standard, for silica was importantly influenced by the previous studies, we believe that adoption of this standard would be premature.

Evaluation of the surface roughness of cystine stones using a visible laser diode scattering approach.

To understand the processes of fragmentation and the chemical reactivity of solids, proper characterization of surface topography is crucial. This paper describes a non-destructive technique of quantifying the surface roughness of cystine renal stones, using visible laser diode scattering and fractal geometry. Fragments of cystine stones were mounted on microscope slides and coated by a carbon-sputtering apparatus. The slides were placed under a dynamic active-vision system, using a visible laser diode to measure three-dimensional surface coordinates. The data obtained were analyzed by fractal geometry. Surface fractal dimensions were determined by the variation method. The results showed that the surface of a compact-size sample can be evaluated quantitatively. The technique is valuable for the accurate presentation of surfaces in three dimensions.