AMSA: in vivo log cell kill for leukemic clonogenic cells versus toxicity for normal hemopoietic stem cells in a rat model for human acute myelocytic leukemia (BNML).

The efficacy of AMSA was evaluated quantitatively in a rat model (BNML) relevant for human acute myelocytic leukemia. The LD50 values observed in normal and leukemic Brown-Norway rats were 26.4 and 28.3 mg/kg respectively. In the higher dose ranges, the major cause of death was acute cardio-pulmonary toxicity. After single dose treatment, 20 mg AMSA/kg resulted in a surviving fraction of 5.5 X 10(2) for normal pluripotent hemopoietic stem cells and 4.1 X 10(-5) for in vivo clonogenic leukemic cells. With repeated administration of the drug amounting to the same total dose, even a 4 log difference in cell kill was observed between both cell populations. These studies provide quantitative information on the therapeutic index of AMSA and support the inclusion of this drug in first-line treatment regimens for acute myelocytic leukemia.

Effects of cyclosporin A on autoimmune disease in MRL/1 and BXSB mice.

MRL/1 and BXSB mice were treated daily with cyclosporin A (CyA) in an oral dose of 25 mg/kg body weight. With this dose, blood levels within the therapeutic range were obtained. In normal mice CyA in this dose significantly prolonged the survival of an H-2 incompatible skin graft, and suppressed delayed-type hypersensitivity (DTH). It had no influence on the magnitude of a primary antibody response. Autoimmune mice were treated from 6 to 22 weeks of age. CyA treatment did not alter significantly the anti-DNA and anti-IgG autoantibody levels in either strain compared with control mice, who received olive oil. There was a slight but significant increase in serum IgG levels in CyA-treated MRL/1 mice. Clinical signs of glomerulonephritis (decreased kidney function and albuminuria), and glomerular proliferation were not altered by CyA treatment in either strain. The amount of mesangial IgG deposits was reduced in CyA-treated MRL/1 mice, and remained unchanged in BXSB mice. The extent of the interstitial and perivascular infiltrates and the frequency and severity of necrotizing arteritis in the kidneys of MRL/1 mice were reduced by CyA treatment. The most prominent effect of CyA was an evident reduction in lymphoproliferation in MRL/1 mice. Mortality was not reduced by CyA treatment in MRL/1 and BXSB mice.

Studies of the effect of mitoxantrone on adjuvant induced arthritis in rats.

When rats with developing or established adjuvant arthritis are treated with mitoxantrone, the hind paw inflammation associated with the disease is inhibited. Radiographic analysis of the hind paws indicates that the agent suppresses joint destruction associated with the lesion. Comparative studies with cyclophosphamide indicate that mitoxantrone is more efficacious and at least 20 times more potent than cyclophosphamide. Mitoxantrone also appeared more effective when given by the subcutaneous route than the peritoneal route of administration.

Cyclosporin A treatment of an induced attack in a chronic relapsing model of experimental allergic encephalomyelitis.

Chronic relapsing experimental allergic encephalomyelitis (EAE) was induced in 8-week-old SJL/J mice by injecting an encephalitogenic emulsion on Day 0 and Day 7. A third injection was given on Day 70 postinoculation (PI) which precipitated an attack with high mortality (62%) after 7-9 days. Cyclosporin A (CsA) was given at doses of 5, 2, and 0.5 mg per mouse, one or three times per week starting from Day 40 PI and continuing over the next 17 days. High serum levels of CsA were measured by radioimmunoassay. However, gross and microscopic pathological examination showed no indication of hepatic or renal toxicity at these doses. In the CsA-treated mice, there was a dose-dependent shortening of the length and severity of the attack forced by challenge with the third injection. The mortality was significantly (P less than 0.05) reduced when compared with the non-CsA-treated controls. In addition, the data demonstrate a decrease of lymphocyte-derived chemotactic factor produced from phytohemagglutinin-stimulated spleen cells of mice with chronic relapsing EAE treated with CsA when compared to normal mice and mice with chronic relapsing EAE treated with vehicle alone. We conclude that it is possible to effect an induced acute attack in ongoing chronic relapsing EAE with CsA treatment.

Preclinical assessment of antiarrhythmic drugs.

The morbidity statistics for the United States alone would suggest that there are 400,000 victims each year who succumb to sudden coronary death, which suggests that there is a need for the development of pharmacological interventions capable of preventing ventricular fibrillation (VF) in patients identified as being at high risk. A major deficiency in this area of experimental investigation is the lack of an animal model that would permit preclinical studies to identify potentially useful therapeutic agents. We have developed an experimental canine model of sudden coronary death in which VF occurs in the chronically injured heart that is subjected to a period of transient ischemia in a coronary region remote from the site of a previous myocardial infarction. The experimental model is subject to the induction of ventricular tachyarrhythmias in response to programmed electrical stimulation, thereby permitting the investigator to correlate the effectiveness of a pharmacological agent in preventing electrically induced arrhythmias with its potential to prevent the development of VF in response to ischemia at a site remote from a previous infarct. Thus, acute myocardial ischemia at a site distant from a previous myocardial infarction enhances the likelihood of primary VF in the conscious dog. This model of sudden coronary death may stimulate more closely the clinical state in humans and might serve as an appropriate model for the study of electrophysiological mechanisms associated with the development of VF and for the evaluation of potential antifibrillatory drugs.

Experimental aspects of intraabdominal abscess.

Two animal models were used to examine the bacteriologic aspects and antibiotic treatment of intraabdominal abscess. The first model was designed to simulate the septic complications of colonic perforation using an inoculum of stool implanted intraperitoneally in rats. The results showed that coliforms were responsible for early lethality, Bacteroides fragilis appeared to play a particularly important role in abscess formation, and optimal treatment required antimicrobial regimens directed against both coliforms and anaerobes. The second model was designed to examine the pharmacokinetic properties of antibiotics and therapeutic efficacy of various antimicrobials in a subcutaneous abscess involving B. fragilis in mice. This work showed all drugs penetrated abscesses, although there was a diminishing antimicrobial effect with progressive delays in the time that treatment was initiated. It is suggested that bacteria within an abscess are in a stationary phase of growth so that early institution of treatment is critical for optimal in vivo activity, and bactericidal drugs may be preferred once an abscess has formed.