Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study.

This open, multicentre, randomized phase II trial was conducted to determine the effect of isolated limb perfusion (ILP) with tumour necrosis factor-alpha (TNFalpha) in combination with melphalan with or without interferon-gamma (IFNgamma) in patients with in-transit metastases of melanoma of the limbs (MD Anderson stage IIIA or IIIAB, AJCC stage III). The 64 patients included were randomized to receive either a two- drug regimen consisting of TNFalpha and melphalan (TM-ILP) or a three-drug regimen consisting of TNFalpha, melphalan and INFgamma (TIM-ILP). Patients randomized to receive IFNgamma were pretreated for 2 days before the ILP with once daily 0.2 mg IFNgamma subcutaneously and also received the same amount of IFNgamma during ILP. A total of 47 complete responses (73%) were reported, 22 (69%) of which occurred in the TM-ILP group and 25 (78%) in the TIM-ILP group; the difference was not significant. The 14 partial responses (22%) were split evenly between the treatment groups. In the TM-ILP group, two cases of stable disease and one case of progressive disease were reported. The overall response rate (complete plus partial responses) was 100% in the TIM-ILP group and 91% in the TM-ILP group, yielding an overall response of 95% for this study. In the historical control data, where 103 patients had received melphalan alone (M-ILP), there were 54 records of complete responses (52%) and 80 of complete or partial responses (78%). The median survival time estimated by the Kaplan-Meier method was 819 days for the TM-ILP group, > 705 days for the TIM-ILP group and 873 days for the combined study population; estimates for time to local progression or recurrence were 327 days, in excess of 498 days and 405 days, respectively. The corresponding figure for the historical controls was 338 days. These data suggest that TNFalpha associated with melphalan may be superior to melphalan alone for ILP.

Enoxacin: worldwide in-vitro activity against 22451 clinical isolates.

A worldwide multicentre study involving 31 centres in eight countries was conducted to compare the in-vitro activity of enoxacin with that of other currently available antibiotics. Enoxacin was active against virtually all of the species of Enterobacteriaceae tested (MIC90 less than or equal to 0.25-2 mg/l). It was also effective at inhibiting Pseudomonas aeruginosa (MIC90 = 2 mg/l; n = 3540), Staphylococcus aureus and epidermidis (MIC90 = 2 mg/l; n = 2635 and 837 resp.), Acinetobacter calcoaceticus (MIC90 = 4 mg/l; n = 260), Neisseria gonorrhoeae and Haemophilus influenzae (both MIC90 less than or equal to 0.25 mg/l). The MIC90 for enoxacin against streptococci ranged from 8 to 32 mg/l. Comparison of data from Canada, West Germany, U.K., South Africa and New Zealand showed the MICs for enoxacin to be generally consistent throughout the world. The only exception was for Citrobacter freundii where the MIC90 was significantly higher in the U.K. than in West Germany (P less than 0.05 Mann Whitney U Test). Against susceptible species the activity of enoxacin was generally greater than that of ampicillin, gentamicin and the cephalosporins. Because of the prevalence of resistance to these drugs, there appears to be a continued need for new antibiotics with differing mechanisms of action.

Flunarizine in the treatment of vertigo.

Experience with flunarizine, a selective calcium-entry blocker, in the treatment of dizziness is reviewed. Clinical efficacy was predicted in pharmacological studies both in rabbits and humans: torsion swing or caloric induced nystagmus were significantly suppressed by flunarizine. Open therapeutic findings, using clinical and electronystagmographic or audiographic assessments as well, showed that flunarizine is of benefit to patients with vertigo of labyrinthine as well as of cerebrovascular origin. These results were confirmed in double-blind controlled trials. Flunarizine, either started with a loading dose gradually decreased thereafter, or given at a fixed 10 mg. dose schedule was proven to produce rapid improvement of dizziness and unsteadiness and to be tolerated very well.

Lorcainide (R 15 889), a first review.

This is a first review of lorcainide hydrochloride, a new antiarrhythmic agent with local anaesthetic activity. The antiarrhythmic actions of lorcainide are mediated by an impairment of fast sodium conductance. Pharmacologically, this drug appears effective in suppressing reentry phenomena and ectopic pacemaker activity, especially in the ventricles. Lorcainide has only negligible depressant effects on important haemodynamic parameters and its toxicity is minimal. The drug is well absorbed by the oral route and its elimination half-life is long when compared with other substances. Lorcainide-induced QRS widening is directly correlated with the plasma levels of the drug. Preliminary experience in supraventricular arrhythmias is promising but pre-excitation syndromes and the ventricular arrhythmias are the main indications for this drug since a very high response rate has been observed in these conditions. Side effects are harmless and dose-dependent, but may be clinically troublesome.

In vitro chemosensitivity tests on xenografted human melanomas.

An in vitro chemosensitivity test has been applied to malignant melanoma cells from 5 patients. The tumour cells were first grown as xenografts in immune-suppressed mice, so that the results of the in vitro test could be compared with precise measurements of the sensitivity of the melanoma cells when exposed to chemotherapeutic drugs in vivo in the mouse. The in vitro assay involved exposing the tumour cells to each of 8 drugs, after which cell survival was determined by colony assay in soft agar. Dose-response curves were obtained and the surviving fraction at drug levels estimated to be achieved in man was used as a measure of in vitro drug sensitivity. Significant differences among the 8 drugs were detected, and these accorded with clinical experience. The correlation of in vivo (in the mouse) and in vitro sensitivities to Melphalan and MeCCNU was also significant.