A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer.

PURPOSE: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 administered at different doses in two different schedules to patients with advanced cancer. EXPERIMENTAL DESIGN: Cohorts of three to four patients were given escalating doses of rhIL-18 as a 2-h i.v. infusion either on 5 consecutive days repeated every 28 days (group A) or once a week (group B) for up to 6 months. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic measurements. RESULTS: Nineteen patients (10 melanoma and 9 renal cell cancer) were given rhIL-18 in doses of 100, 500, or 1,000 microg/kg (group A) or 100, 1,000, or 2,000 microg/kg (group B). Common side effects included chills, fever, headache, fatigue, and nausea. Common laboratory abnormalities included transient, asymptomatic grade 1 to 3 lymphopenia, grade 1 to 4 hyperglycemia, grade 1 to 2 anemia, neutropenia, hypoalbuminemia, liver enzyme elevations, and serum creatinine elevations. No dose-limiting toxicities were observed. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-gamma, granulocyte macrophage colony-stimulating factor, and IL-18-binding protein were observed following dosing. CONCLUSIONS: rhIL-18 can be given in biologically active doses by either weekly infusions or daily infusions for 5 days repeated every 28 days to patients with advanced cancer. Toxicity was generally mild to moderate, and a maximum tolerated dose of rhIL-18 by either schedule was not determined.     

High frequency oscillation in newborn infants with respiratory failure

Objective: To report ventilation strategies, survival and complications in 39 outborn infants treated with high frequency oscillatory ventilation (HFOV).
Methodology Data were collected prospectively between 1 May 1992 and 31 December 1993 on all infants treated with HFOV who had severe respiratory failure despite optimal conventional ventilation.
Results Twenty-eight out of 39 (72%) survived. Of the 15 infants with birthweights <1500g, eight survived. Best survival rates were for infants with pulmonary interstitial emphysema with air leak (4/5) and for infants of birthweight >1500g with hyaline membrane disease (8/8), and meconium aspiration syndrome (7/7). Three infants deteriorated while on HFOV and required extracorporeal membrane oxygenation. Complications were: (i) development of pulmonary interstitial emphysema (1); (ii) recurrence of pneumothorax (3); (iii) hypotension (2); and (iv) bronchopulmonary dysplasia (9). One of the eight infants weighing <1500g who received HFOV in the first week of life developed periventricular haemorrhage.
Conclusion The initial results of HFOV for severe respiratory failure were encouraging although a learning curve was encountered with its introduction.     

In vitro and in vivo antimalarial activity of cryptolepine,a plant-derived indoloquinoline

Cryptolepine is an indoloquinoline, high yields of which may be extracted from the roots of the West African shrub Cryptolepis sanguinolenta. The use of this plant as a traditional treatment for malaria is widespread in Ghana and is reported to be clinically effective. We have tested cryptolepine for in vitro antiplasmodial activity against the multidrug resistant (K1) strain of Plasmodium falciparum and found it to be highly active with an IC₅₀ value of 0.031±0.0085 (SE) μg/mL, equivalent to 0.134±0.037 μM (n = 3). In a 4-day suppression test there was, however, no significant reduction in parasitaemia in P. berghei-infected mice treated subcutaneously with cryptolepine (7–113 mg/kg/d×4), when compared with untreated controls. Like 9-aminoacridine, this compound appears to intercalate with DNA and this may explain the high degree of antimalarial activity demonstrated in vitro.     

Prenatal diagnosis of non-ketotic hyperglycinemia

We describe successful prenatal diagnosis in four pregnancies at risk for non-ketotic hyperglycinemia, two affected and two unaffected, using the glycine level and the glycine/serine ratio in amniotic fluid obtained at 16 weeks gestational age. Although this method of prenatal diagnosis for non-ketotic hyperglycinemia has been effective in our hands the narrow differences between affected and unaffected pregnancies indicate the need for caution concerning its reliability.     

Cryopreservation of human embryos: Progress on the clinical use of the technique in human in vitro fertilization

Embryo cryopreservation has been studied at Monash University since 1981 and has been available to patients since mid-1983. Of approximately 1200 patients' cycles of in vitro fertilization (IVF), 445 have had excess embryos which they requested to be frozen. To date 205 patients have requested thawing of their embryos and 144 have had frozen-thawed embryos replaced in utero, resulting in 16 pregnancies. Four of these pregnancies aborted, four are ongoing, and eight deliveries have resulted, including one stillbirth at 26 weeks and one set of twins. Analysis of the data collected to date shows that patients with three or more embryos frozen have a significantly higher pregnancy rate than patients with one or two embryos frozen (23 versus 4%, respectively). Embryo viability, but not embryo survival, following freezethawing is related to the degree of embryonic fragmentation and the cell stage at freezing. Eight-cell embryos had a significantly higher viability than other cleavage stages. Those resulting in pregnancy tended to be the faster-dividing eight-cell embryos and were undamaged after freezing and thawing. However, when considering all cleavage stages, there was little effect of freezing damage on embryo viability, providing that at least 50% of the cell complement of embryos were intact and the zona pellucida was undamaged. Nor was there any marked effect of the age of embryos postinsemination. It is also possible that patients who were pregnant following the initial embryo replacement on the cycle of IVF treatment are more likely to conceive following replacement of their frozen-thawed embryos.     

Culture factors in relation to the success of human in vitro fertilization and embryo transfer

The development of 1-cell mouse zygotes to the blastocyst stage in vitro has been used as a quality control for the media employed for human in vitro fertilization and embryo transfer (IVF-ET). The following procedures were associated with high rates of mouse embryo development and human pregnancies following IVF-ET: adequate gassing and equilibration of the medium, double rinsing of pipettes and catheters used to handle embryos, use of a HEPES-buffered medium for manipulating embryos in the absence of an atmosphere containing 5% CO2, control of excessive temperature in the vicinity of the embryos, and ET using medium containing 50% patient's serum. The institution of these procedures gave more consistent pregnancy rates. However, there was no obvious association between fertilization and cleavage of human oocytes and the quality of the medium ascertained by the mouse embryo development test.     

Arteriovenous malformation mimicking a renal-cell carcinoma

We describe a renal arteriovenous malformation in a patient with a 1-month history of flank pain. Imaging studies were interpreted as being consistent with renal-cell carcinoma. However, Doppler ultrasonography demonstrated turbulent blood flow, and selective renal angiography confirmed the diagnosis of an arteriovenous malformation. Embolization relieved the pain. This case calls attention to the need to consider arteriovenous malformations in the differential diagnosis of central homogenously enhancing renal lesions.     

Evidence for corticotropin-releasing factor regulation of serotonin in the lateral septum during acute swim stress: adaptation produced by repeated swimming

RATIONALE: Swim stress decreases extracellular serotonin (5-HT) levels in the rat lateral septum, and adaptation to this effect occurs with repeated swimming. Corticotropin-releasing factor (CRF) administered into the dorsal raphe nucleus (DRN) also decreases 5-HT release in the lateral septum, suggesting that CRF may mediate the effects of swim stress. OBJECTIVES: The hypothesis that endogenous CRF mediates the reduction of 5-HT levels in the lateral septum evoked by swim stress and is involved in the adaptation that occurs with repeated swim stress was tested. METHODS: Extracellular 5-HT levels in rat lateral septum were quantified by means of in vivo microdialysis. Extracellular single unit activity was recorded from the DRN. RESULTS: Intracerebroventricular (i.c.v.) administration of a CRF receptor antagonist prevented the ability of swim stress to decrease 5-HT release in the lateral septum. Prior exposure to swim stress reduced the ability of both CRF (i.c.v.) and a subsequent swim stress to decrease lateral septum 5-HT release (cross adaptation). Additionally, the effects of CRF, administered into the DRN, on DR neuronal discharge were attenuated in rats with a history of swim stress. Finally, administration of a CRF receptor antagonist (i.c.v.) between two swim stress sessions restored the neurochemical response to swim stress (i.e., 5-HT levels were reduced during the second exposure to swim). CONCLUSIONS: Endogenous CRF modulates 5-HT transmission during acute environmental stress and is also integral to adaptation of the 5-HT response produced by repeated stress. Modulation of the 5-HT system by CRF during acute stress may underlie certain coping behaviors, while stress-induced adaptation of this effect may be involved in psychiatric manifestations of repeated stress.     

Where do we go from here?

In the past two and a half years since the Senate Committee began its study of the Canadian healthcare system, an abundance of reports on healthcare, at both the provincial and federal levels, have been issued that have provided the public and policy-makers with a comprehensive overview of the key issues and the main options for change. We have clearly reached a point where action of some sort can no longer be deferred on the grounds that further study is necessary. It is now a question of finding the political will to move forward with reform.