Dichloroacetate and cerebral ischaemia therapeutics.

Brain ischaemia is a major medical problem which totally lacks meaningful therapeutic options. A drug that reduces morbidity and mortality associated with head injury and stroke would constitute a major medical breakthrough. Although many mechanistic approaches have been evaluated clinically for both stroke and head injury, none have yet to be proven successful. Dichloroacetate (DCA, Ceresine) is a small molecule that activates pyruvate dehydrogenase (PDH) and crosses the blood-brain barrier. PDH activation reduces neurotoxic lactic acidosis which always accompanies brain ischaemia. DCA shows substantial efficacy in a variety of models of stroke, pre-stroke, head or spinal cord injury. Agents that lower cerebral lactic acidosis have not yet been clinically evaluated in head injury and stroke, although DCA has been shown clinically to reduce ambient lactate concentrations in patients with such conditions. DCA has also been shown to be well-tolerated in these patients, and unlike many halogenated molecules, is not mutagenic. Since elevated brain lactate is correlated with poor outcome in both preclinical and clinical studies, an agent such as DCA may prove to reduce the brain injury associated with these disorders. Potential clinical applications of DCA include stroke, head injury, spinal cord injury, and chronic disorders such as congenital lactic acidosis (CLA) and mitochondrial lactic acidosis and stroke-like syndrome (MELAS).

Potential therapeutic applications of fructose-1,6-diphosphate.

Ischaemia-related tissue injury is the leading cause of death in developed countries. Drugs that can reduce ischaemic injury would be beneficial in treatment of myocardial infarction (MI), surgical trauma and stroke. Fructose-1,6-diphosphate (FDP) is a key intermediate in anaerobic glycolysis and is the product of the major regulatory enzyme in the pathway (phosphofructokinase). Preclinical and clinical data suggest that FDP has substantial cytoprotective effects in a variety of ischaemia-reperfusion injury scenarios. Evidence indicates that FDP has a direct effect on ATP pools, reduces ischaemia-induced tissue damage and has positive inotropic effects on heart function. The clinical data suggest that FDP may be a useful drug in a variety of ischaemic and inflammatory clinical settings where acute management of tissue injury is desired. Potential uses include: iv. administration for the reduction of ischaemic injury in sickle cell anaemia, bypass surgery, congestive heart failure, myocardial infarction, as well as organ preservation in transplants.

The influence of blood chemistry on T4 and FT4I in major depression.

The pathophysiology underlying thyroid dysfunction in some depressed patients has not yet been determined. In order to clarify possible biochemical influences on thyroid regulation in these patients, we retrospectively examined several thyroid indices in charts from 81 depressed inpatients and 82 psychiatric controls. The depressed group had significantly higher T4 levels and free T4 index (FT4I), as well as lower chloride (CL) levels than controls. Albumin (ALB) also tended to be higher in the depressives. After adjustment for previously reported effects of ALB and CL on thyroid hormone binding in plasma, the initial differences in thyroid indices became non-significant. We suggest from these findings that plasma biochemical factors contribute significantly to the transient changes in thyroid function observed in some acutely depressed patients. Potential explanations for these biochemical alterations are discussed.

Intravenous and intramuscular pharmacokinetics of recombinant leukocyte A interferon.

Interferon is currently being evaluated for the treatment of disseminated cancer and viral diseases. Alpha interferons have shown to be effective in the treatment of a number of malignancies. Recombinant leukocyte A interferon (rIFN-alpha A) is an alpha interferon produced by recombinant DNA techniques. A kinetic evaluation of rIFN-alpha A following intravenous and intramuscular administration has not been adequately defined. The present study was designed to evaluate the kinetics of rIFN-alpha A following intravenous and intramuscular administration of 3, 9 or 18 X 10(6) units to patients with disseminated cancer. A preliminary report of this study was presented at the meeting of the American Society for Clinical Pharmacology and Therapeutics in San Diego, March 1983 (1).