Extravasation of dactinomycin, vincristine, and cisplatin: studies in an animal model

Extravasation of some cytotoxic drugs results in chemical cellulitis. Management of suspected extravasation has been empiric and difficult to evaluate clinically. We investigated dactinomycin, vincristine, and cisplatin by means of intradermal injections in Balb-c mice. Reproducible skin lesions with concentric areas of induration, erythema, and ulceration developed in a time- and dose-dependent fashion following injection of dactinomycin. Vincristine caused no lesions following initial intradermal administration, but repeat injection 7 days later was followed by a diffuse punctate ulcerative lesion suggesting a hypersensitivity reaction. Three concentrations (1.0, 0.1, and 0.01 mg/ml) of cisplatin elicited cellulitis following initial injection, but there was no correlation between lesion size and dose. Injection of saline, hydrocortisone, ascorbic acid, sodium thiosulfate, buffered DNA solution, and beta adrenergic agonists and antagonists after the injection of dactinomycin failed to prevent development of lesions. Heat application was also ineffective; however, local cold application prevented or markedly reduced reactions to dactinomycin. We conclude that the intradermal mouse model may be appropriate for the evaluation of the three drugs studied and that cold application is the best antidote among those tested for dactinomycin-induced ulceration in this model.     

Cytosine arabinoside/cyclophosphamide pulses during continuation therapy for childhood acute lymphoblastic leukemia. Potential selective effect in T-cell leukemia

One hundred seventy-seven children with acute lymphoblastic leukemia (ALL) were admitted to a study designed to determine whether pulses of cytosine arabinoside (ara-C) and cyclophosphamide (cyclo) would improve disease-free survival (DFS). All patients received vincristine, prednisone, and asparaginase for remission induction, CNS prophylaxis with cranial irradiation and intrathecal methotrexate, and continuation therapy with 6-mercaptopurine plus methotrexate. Forty-seven of 101 patients with non-T ALL and 18 of 26 patients with T-cell ALL received ara-C/cyclo pulses every eight weeks during continuation therapy. The age, sex, and initial white cell count distributions were similar in both treatment groups. Patients with non-T-cell ALL had similar DFS with or without ara-C/cyclo pulses (36% versus 48%; P = 0.32). Ara-C/cyclo pulses significantly improved DFS in children with T-cell ALL (36% versus 0%; P = 0.015). Toxicities of the ara-C/cyclo pulses included reversible pancytopenia, drug induced fever, fever associated with neutropenia, and death in one patient from systemic candidiasis while neutropenic. This is the first clinical evidence to indicate that the combination of ara-C/cyclo used during continuation therapy is selectively beneficial in T-cell ALL.     

Meal-stimulated neurotensin immunoreactivity in plasma following gastric surgery: characterisation with two region-specific antisera

Plasma neurotensin (NT) response to a simple fatty meal, administered via an indwelling naso-gastric tube, has been assessed in two groups of subjects following gastric surgery without resection, and in healthy controls. Two region-specific NT antisera were employed in the radioimmunoassay (RIA) of plasma samples. The first, NT3, recognises only NT 1-13 in plasma extracts, while the second, GNT 21, recognises NT 1-13, NT 1-11 and NT 1-8 equally. In addition, plasma extracts were subjected to reverse-phase high performance liquid chromatography, fractions from which were subjected to each region-specific RIA. There was no significant response to the test meal in the healthy controls. However, both groups of post-gastric surgery subjects, who had undergone either vagotomy and pyloroplasty (V & P) or vagotomy and gastrojejunostomy (V & GJ), displayed significant increases in both intact and N-terminal plasma NT immunoreactivity (IR). The integrated responses of the V & P and V & GJ groups were also significantly higher than the control response but did not differ significantly from one another. The proportion of intact NT to total N-terminal NT-IR in each group was not significantly different.     

A low molecular weight heparin alters the fetal coagulation system in the pregnant sheep

Standard heparin and a LMWH, CY222 do not cross the placenta nor alter fetal coagulation when injected into the pregnant ewe. We found that another LMWH, Pharmuka-10169 (PK-10169) alters fetal coagulation without crossing the placenta in the pregnant sheep. To characterize this anticoagulant we measured the in vitro and in vivo effects of 125I-PK-10169 in maternal and fetal plasmas following administration of PK-10169 to the mother or fetus. The fetal anticoagulant activity was not neutralizable by protamine sulphate and was attributable to the inhibition of thrombin but not factor Xa. In vitro, the fetal anticoagulant activity had properties similar to dermatan sulphate; both catalyzed the inhibition of thrombin but not factor Xa by sheep plasma; and neither was neutralizable by protamine sulphate. These effects were due to the enhanced neutralization of thrombin by heparin cofactor II. We conclude that PK-10169 does not cross the placenta, but does induce the release of an endogenous dermatan sulphate-like substance which alters fetal coagulation.     

Hypothermia is critical for survival during prolonged insulin-induced hypoglycemia in rats

Hypothermia is a well-known concomitant of hypoglycemia in mammals. We tested the hypothesis that this hypothermia is an important adaptive response to hypoglycemia in 11 normal Sprague-Dawley rats. Twelve-hour fasted, conscious animals received primed, continuous insulin infusions for up to 8 hours. Plasma glucose was clamped between 30 and 40 mg/dL and core body temperature was monitored continuously during the insulin infusions. Five of the animals were maintained in a room temperature environment (22 to 24 degrees C) during the hypoglycemia; all became hypothermic (mean +/- SE nadir core temperature, 31 +/- 0.5 degrees C). Spontaneous activity was reduced in these animals, but they remained conscious and responsive to external stimuli. All five returned to normal behavior after euglycemia was restored at the end of the insulin infusions. In the remaining six animals, hypothermia was prevented during hypoglycemia by warming of the air in their cages (mean of hourly core temperatures, 37 +/- 0.1 degrees C). None of these animals survived more than 7 hours. The severity of the hypoglycemia was no greater in the euthermic than in the hypothermic group, as judged by the mean of individual nadir plasma glucose levels (25 +/- 1 v 24 +/- 1 mg/dl, respectively) and by the mean number of glucose values per animal that were less than 30 mg/dL (2 +/- 1 v 7 +/- 1). Plasma osmolality did not change significantly in either group during the period of hypoglycemia, suggesting that dehydration was not the cause of death in the euthermic animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sustained attention and inhibitory control in children with sickle cell syndrome.

Comparing sustained attention and inhibitory control among youth with sickle cell syndrome (SCS) and nondiseased sibling controls, this study found significant differences in multiple components of attention and inhibitory control as a function of chronological age. Older SCS youth were found to have increased attention and reflectivity. Although it has been argued that SCS youth without overt neurological impairments might evidence microvascular infarction, the present study, which employed commonly utilized neurocognitive and behavioral measures, does not lend support to the notion of generalized deficits in the absence of specific laboratory findings. Disease parameters including hemoglobin levels, days hospitalized, and emergency room visits were not significantly correlated with performance on any of the measures. Within the limitations of this particular study, results were interpreted to refute the notion of disease-related neurocognitive impairments for SCS youth. Further, the development of attentional skills for SCS youth is suggested to proceed similarly to that of normally developing youth.