Plasma lonidamine concentration and toxicity were investigated in dogs receiving 100, 200, 400, 800, 1200 mg/m2 orally twice daily for 30 days and in dogs receiving single intravenous doses of 200, 400, 800, 1200 mg/m2. Physical or laboratory signs of toxicity were not observed in dogs receiving oral lonidamine, but severe vomiting and signs of acute hepatic and pancreatic toxicity were observed in dogs receiving intravenous doses that exceeded 400 mg/m2. The area under the lonidamine concentration versus time curve (AUC) in dogs receiving 200, 400, and 800 mg/m2 of lonidamine intravenously was a 1.8-, 3.3-, and 8.7-fold higher than in dogs receiving oral lonidamine. This suggests that the bioavailability of oral lonidamine may be limited. However, centrilobular hepatocellular swelling and vacuolation were observed in dogs receiving oral lonidamine. Serum alanine aminotransferase (ALT) activity was increased in dogs receiving intra-venous lonidamine. These findings suggest that lonidamine is hepatotoxic in dogs. However, serum ALT was increased in only 1/4 dogs receiving 400 mg/m2 of lonidamine intravenously and plasma concentration were within the range capable of sensitizing hyperthermia and chemotherapy. Therefore, this dose and route appears to be a viable and controllable method for prospective quantification of lonidamine interaction with systemic chemotherapy and/or hyperthermia.

The maximum tolerated dose of melphalan combined with whole body hyperthermia (WBH) in dogs with spontaneous malignant melanoma was lower than in dogs not receiving WBH by a factor of 1.9 +/- 0.71. Thirty-three dogs were treated monthly with escalating doses of melphalan and followed weekly for toxicity and, when possible, tumour response. Toxicity was manifested as myelosuppression with nadir neutrophil and platelet counts occurring at 7-10 days post-treatment. The TD50 (+/- S.E.), defined by logistic regression analysis, was 0.63 (+/- 0.07) mg/kg and 0.33 (+/- 0.10) mg/kg for melphalan alone and combined with WBH, respectively. Objective tumour response in this limited series occurred in three of fourteen evaluable dogs (three of eleven treated with melphalan alone and none of three treated with WBH plus melphalan). It is concluded that melphalan combined with WBH can be safely administered, although a reduction in dose is necessary. A randomized clinical trial is required to investigate the possibility of achieving therapeutic benefit from combined melphalan and WBH.

Summary1. When anticoagulated blood is placed in a rotating glass flask, the blood/air interface initiates platelet aggregation, and the aggregates are trapped on the flask wall, without adhering to it, by the thin film of blood which forms during rotation. The interface; allows CO2 loss so that the pH of the rotating blood rises markedly and this rise is associated with the release of 3H-5HT from platelet. When CO2 diffusion and consequent pH rise is prevented, platelet loss and 3H-HT release are significantly reduced.2. A simple method for assessing the adhesiveness of single platelets to glass using a Neubauer haemocytometer chamber has been developed. The results obtained are independent of platelet number which allows the test to be used in conditions in which abnormal platelet behaviour is associated with a low platelet-count.3. Adhesiveness was negligible in heparinised PRP, and was greater in EDTA PRP than in citrated PRP. Heparin abolished the increased adhesiveness observed with the other anticoagulants and adhesiveness did not seem to be directly related to residual plasma calcium concentrations. Platelets adhered more readily to siliconised glass surfaces than to untreated glass, and adhesion was markedly temperature-dependent, being maximal at 4°C in heparinised PRP, and at 20° C in EDTA PRP.4. Adhesiveness was enhanced by aggregating agents, this enhancement being prevented by inhibitors of aggregation such as the dipyridamole analogue VK 774. Adhesiveness was unaffected by acetyl-salicylic acid.5. Adhesiveness increased markedly after surgical operations and myocardial infarction. Within-person variation was considerable, and the test is of no value in individual patients.

The purpose of this study was to examine if ATP-MgCl2, an agent that protects against acute cisplatin toxicity in vitro, protected against cisplatin toxicity in vivo. Baseline renal function measurements were obtained on dogs (n = 12) and rats (n = 20) on day -1. Dogs were given 90 mg m-2 cisplatin (n = 5), 90 mg m-2 cisplatin and 50 mumol kg-1 ATP-MgCl2 (n = 5), or 90 mg m-2 cisplatin and 150 mumol kg-1 ATP-MgCl2 (n = 2), in a slow bolus i.v. injection on day 0. Rats were given 4 mg kg-1 cisplatin i.p. (n = 6) and 25 mumol kg ATP-MgCl2 (n = 8) i.v. or 4 mg kg-1 cisplatin i.p. and 25 mumol kg-1 ATP-MgCl2 (n = 6) i.v. on day 0. Renal function was assessed on a routine basis for 14 days. All dogs had significantly decreased creatinine clearance following cisplatin administration. There were no significant differences in renal function tests between groups of dogs. One dog given 50 mumol kg-1 ATP-MgCl2 and both dogs given 150 mumol kg-1 ATP-MgCl2 in addition to cisplatin developed acute anuric renal failure and were euthanatized prior to completion of the study. Rats given 4 mg kg-1 cisplatin and 25 mumol kg-1 ATP-MgCl2 had significantly increased blood urea nitrogen and serum creatinine after drug administration, compared to rats given cisplatin alone. The results indicated that ATP-MgCl2 worsened in vivo cisplatin renal toxicity in the dog and rat.

No abstract