Neurotoxic envenoming by an immigrant spider (Steatoda nobilis) in southern England.

A young woman was bitten on the shoulder by a female Steatoda nobilis spider, in Worthing on the south coast of England. She noticed intense radiating pain, local sweating (indicating parasympathetic stimulation) and feverishness. This immigrant species from the Canary Islands has established itself along the south coast of England in recent years. Like the related Mediterranean species S. paykulliana, S. nobilis may be of medical importance and deserves further study.     

Rediscovery and redefinition of Malcolm Smith's Trimeresurus kanburiensis in Thailand, with a report of envenoming.

Three specimens of an apparently rare pit viper, Trimeresurus kanburiensis, previously known only from the holotype collected in 1928, were found near Kanchanaburi in western Thailand. One of the snakes had bitten a young woman on the foot. She experienced severe local pain, swelling that involved the whole of the bitten limb and beyond, local bruising, recurrent shock, peripheral leucocytosis and a mild coagulopathy, but she recovered despite the lack of specific treatment. The severity of envenoming augurs ill for a young or debilitated patient bitten by this species. During the last 20 years, the name T. kanburiensis has been used incorrectly for the medically more important species, T. purpureomaculatus. Conversely, the name T. purpureomaculatus has been misapplied to specimens of a species of viper from southern Thailand which we consider very similar to T. kanburiensis, but for which a new specific name, 'T. venustus', has been suggested recently. The rediscovery and redefinition of T. kanburiensis should prevent further confusion.     

Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia.

Although all-trans retinoic acid (RA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL), all groups have described clinical relapses despite continued RA treatment. This finding suggests that resistance to the cytodifferentiating effects of the retinoid had been acquired. To investigate potential mechanisms of clinical resistance to RA, we serially evaluated the clinical pharmacology of the drug in APL patients treated with this agent. Leukemic cells from patients relapsing from RA treatment were cultured in the presence of RA and examined for evidence of morphologic maturation. We also studied messenger RNA expression of the newly described gene product of the (15;17) translocation in APL, PML/RA receptor-alpha (PML/RAR-alpha). Serial pharmacokinetic studies showed that continuous daily RA treatment was associated with a marked decrease in plasma drug concentrations at the time of relapse compared with the initial day of therapy. Doubling the RA dose in six patients failed to reinduce response at the time of relapse and also failed to significantly augment plasma RA concentrations. However, leukemic cells obtained at the time of relapse from four patients retained in vitro sensitivity to the differentiating activity of RA (10(-6) mol/L). No change was observed in the pattern of PML/RAR-alpha expression assessed by Northern blot analysis at the time of relapse compared with pretreatment in two patients who were tested. These results indicate that clinical relapse and "resistance" to continuous treatment with all-trans RA in APL is associated with progressive reduction of plasma concentrations, potentially to levels below those that sustain differentiation of leukemic cells in vivo. Long-term success of this treatment will require the development of strategies that circumvent this pharmacologic phenomenon.     

An attempt to treat rabies encephalitis in monkeys with intrathecal live rabies virus RV 675

Summary A highly attenuated rabies virus, RV 675, proved innocuous but immunogenic when injected intrathecally into monkeys by the lumbar route. Attempts to use this virus to modify the course of fatal rabies encephalitis in monkeys were inconclusive possibly because of the brief encephalitic illness. Further studies are indicated to investigate RV 675 as a candidate therapeutic agent for rabies encephalitis.     

Clinical pharmacology of oral all-trans retinoic acid in patients with acute promyelocytic leukemia.

All-trans retinoic acid (RA) induces leukemic cell differentiation and complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). However, remissions induced by all-trans RA tend to be brief, and relapses are associated with resistance to further treatment in vivo, although the leukemic cells appear to retain sensitivity to the cytodifferentiating effects of all-trans RA in vitro. The clinical pharmacology of all-trans RA was examined in 13 patients with APL. The drug was administered at a constant dose of 45 mg/m2/day, given as a single dose on the first day of therapy and in two divided doses thereafter. Plasma and urinary concentrations of the parent drug and metabolites were quantitated by reverse-phase high-performance liquid chromatography and, where required, by a combination of normal-phase liquid chromatography/negative chemical ionization mass spectrometry. In patients with APL, basal levels of endogenous retinol and natural retinoids were within the normal range. Peak plasma levels of all-trans RA (347 +/- 266 ng/ml, mean +/- SD) were reached 1-2 h after drug ingestion and decayed in a monoexponential fashion with a half-life of 0.8 +/- 0.1 h. The only drug metabolite detected in plasma or urine was 4-oxo-all-trans RA (present in urine as the glucuronide conjugate). This metabolite accounted for less than 10% of the circulating drug in plasma, and its cumulative urinary excretion accounted for less than 1% of the administered dose. The drug was not found in cerebrospinal fluid. Continued oral administration of all-trans RA was associated with a significant decrease in both the plasma peak levels and the area under the concentration-time curve (P = 0.01 and 0.004, respectively) when measured after 2-6 weeks of treatment. We previously reported that a decrease in plasma area under the concentration-time curve was highly correlated with clinical relapse. Observations in a subset of patients in this study suggested that, in fact, the major decrease occurred early, within the first 7 days of treatment. These changes were associated with a 10-fold increase in urinary excretion of 4-oxo-all-trans RA glucuronide, suggesting that the accelerated clearance from plasma was associated with increased drug catabolism. The rapid disappearance may explain early relapse from remissions induced by all-trans RA; clinical "resistance" to all-trans RA may either wholly or in part result from an inability to sustain effective plasma concentrations of all-trans RA during continuous treatment.(ABSTRACT TRUNCATED AT 400 WORDS)     

Phase I clinical and pharmacological study of chloroquinoxaline sulfonamide.

Chloroquinoxaline sulfonamide (CQS) is a halogenated heterocyclic sulfanilamide identified by the in vitro human tumor colony-forming assay as an active agent in a variety of human solid tumors. In this phase I study, 182 courses of CQS were administered intravenously every 28 days to 88 patients at doses ranging from 18 to 4870 mg/m2. Hypoglycemia associated with hyperinsulinemia was the dose-limiting adverse effect at 4870 mg/m2. Supraventricular tachyarrhythmias were observed at doses > 4000 mg/m2. Less common reactions included infusion site phlebitis, nausea, anemia, alopecia, perioral numbness, and diarrhea. Cumulative toxicity was not observed. Minor objective antitumor responses were noted in 7 patients; 6 of the 7 responses occurred in patients with non-small cell lung cancer. Results of pharmacokinetic studies were consistent with the preclinical observations that CQS is highly bound to plasma protein. Plasma elimination followed a two-compartment model; the mean t 1/2 alpha was 2.7 +/- 0.3 h and the t 1/2 beta was 52 +/- 6 h (+/- SE). The total body clearance and the volume of distribution at steady state of CQS both increased with the dose (distribution at steady state, 3.7-10.5 liter/m2; total body clearance, 53-264 ml/h/m2 for doses of 18-4060 mg/m2) and may reflect saturation of the protein binding and "free" drug clearance. Although inactive against common animal tumors in preclinical screening systems both in vitro and in vivo, CQS has demonstrated definite activity in the human tumor stem cell colony-forming assays, as well as modest anticancer activity in this phase I study in patients with advanced solid tumors. The pharmacokinetic results and the limiting effect of transient hypoglycemia suggest that considerably higher cumulative doses of CQS could be administered using a more frequent dosing schedule.     

Immunological evaluation of cell-mediated and humoral immunity in Thai patients with cerebral and non-cerebral Plasmodium falciparum malaria: I. Cutaneous delayed hypersensitivity, blood leukocytes and in vitro lymphocyte responses

In Thai patients with acute P. falciparum malaria including cerebral cases, cell mediated immune functions were studied in vivo and in vitro. Initial cutaneous delayed reactions to phytohaemagglutinin and soluble protein antigens were negative in most cerebral malaria patients. No major alteration of the number of circulating T and B cells was observed. In lymphocytes cultures, proliferatives responses to lectins or protein antigens were generally found within normal ranges. This study shows a direct role of P. falciparum on the impairment of cell mediated immunity.     

Haemostatic disturbances in patients bitten by Russell''s viper (Vipera russelli siamensis) in Burma

Patients who are severely envenomed by Russell's viper develop DIC which is frequently associated with spontaneous bleeding and incoagulable blood. These haemostatic disturbances may be responsible for death or organ/tissue damage both through haemorrhage and microvascular occlusion by fibrin thrombi. The most striking laboratory features of the coagulopathy developing after Russell's viper bite in the 42 patients studied were depletion of fibrinogen (mean 0.09 g/l, range 0-0.6), factor V (6.5 u/dl, range 0-17), factor X (35 u/dl, range 1-85), factor XIIIa (57 u/dl, range 15-82), plasminogen (61 u/dl, range 10-92), antiplasmin (36 u/dl, range 14-62). Protein C (49 u/dl, range 15-100) and platelets (104 x 10(9)/l, range 25-197). Intense fibrinolytic activity was detected in all cases with marked elevation of FDPs (1614 micrograms/ml, range 350-3000), a large proportion of which were cross-linked (1058 micrograms/ml, range 38-3000). The monospecific Burmese antivenom appeared to be very effective in neutralizing the venom procoagulants and in restoring blood coagulability. Moreover, the unexpectedly normal level of AT III provides a theoretical basis for the use of heparin to enhance the inactivation of those serine proteases present before antivenom administration.     

Lack of interferon induction in man by two rabies tissue culture vaccines

Both neutralising antibody and interferon play a part in protection of animals against death from rabies virus infection. Interferon induction was therefore sought in 53 volunteers within 24 hours of receiving human diploid cell strain vaccine or fetal bovine kidney cell vaccine given either intramuscularly or intradermally. Repeat observations were made in 18 subjects following a second dose of vaccine seven days later. No interferon was detected in any sample tested although no subject had any detectable rabies neutralising antibody on day 0. The sensitivity of the interferon assay, and comparison with other studies are discussed. An interferon inducer suitable for human use should be sought as an alternative to, or a replacement for, passive rabies immunization.