Dichloroacetate: population pharmacokinetics with a pharmacodynamic sequential link model.

Dichloroacetate (DCA) is a small molecule that reduces ambient concentrations of lactate in man. It was the purpose of this study to develop pharmacokinetic and pharmacodynamic models for determination of a dose for a pivotal Phase III clinical trial of DCA in patients with traumatic brain injury (TBI). Population pharmacokinetic and pharmacodynamic models were developed for DCA using NONMEM software. The pharmacokinetic data were fit to a physiologic two-compartment model, and the pharmacodynamic data were fit to an indirect physiologic response model. Simulations were employed to evaluate various dosing strategies for consideration in a pivotal Phase III clinical trial of DCA. For the pharmacokinetic model, it was discovered that the clearance of DCA decreased on multiple dosing from 4.82 L/h to 1.07 L/h and that the pharmacokinetics and pharmacodynamics in TBI patients could not be predicted from normal volunteers. Population pharmacokinetic modeling and simulation of the expected effects of several dosing strategies were useful procedures for designing a Phase III trial.

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.

Circadian changes in the bioavailability and effects of indomethacin in healthy subjects.

Nine subjects, 19 to 29 years old (2 females) synchronized with activity from 07.00 to 00.00 received a single daily oral dose (100 mg) of indomethacin at fixed hours: 07.00, 11.00, 15.00, 19.00 and 23.00, in random order and at weekly intervals. 1) Chronopharmacokinetics: Venous blood (sampled at: 0, 0.33, 0.67, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0 and 10.0 h post ingestion) was used for plasma drug determination. Circadian changes in peak height, time to peak, area under the concentration-time curve and the disappearance rate were used to characterize indomethacin chronopharmacokinetics. A circadian rhythm of both peak height and time to peak was validated. An evening ingestion led to smallest peak height and longest time to peak. 2) Circadian changes in a set of effects: Eleven physiologic variables were investigated (post absorption) at delta t = 2 h. Circadian rhythms were detected: i) on control day and ii) with evening ingestion for ten of the eleven variables indicating that the subjects' temporal structure did not become altered by an evening ingestion, whereas it did become so by morning ones. Transient changes (n minutes post absorption) measured as T240 min post absorption/Tcontrol day, same clock hour ratio were also circadian rhythmic for most variables. Again, evening ingestion appeared least disturbing.

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.

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).

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).

BCL-2 antisense therapy in patients with non-Hodgkin lymphoma.

BACKGROUND: Overexpression of BCL-2 is common in non-Hodgkin lymphoma and leads to resistance to programmed cell death (apoptosis) and promotes tumorigenesis. Antisense oligonucleotides targeted at the open reading frame of the BCL-2 mRNA cause a specific down-regulation of BCL-2 expression which leads to increased apoptosis. Lymphoma grown in laboratory animals responds to BCL-2 antisense oligonucleotides with few toxic effects. We report the first study of BCL-2 antisense therapy in human beings. METHODS: A daily subcutaneous infusion of 18-base, fully phosporothioated antisense oligonucleotide was administered for 2 weeks to nine patients who had BCL-2-positive relapsed non-Hodgkin lymphoma. Toxicity was scored by the common toxicity criteria, and tumour response was assessed by computed tomography scan. Efficacy was also assessed by quantification of BCL-2 expression; BCL-2 protein levels were measured by flow cytometry in samples from patients. FINDINGS: During the course of the study, the daily dose of BCL-2 antisense was increased incrementally from 4.6 mg/m2 to 73.6 mg/m2. No treatment-related toxic effects occurred, apart from local inflammation at the infusion site. In two patients, computed tomography scans showed a reduction in tumour size (one minor, one complete response). In two patients, the number of circulating lymphoma cells decreased during treatment. In four patients, serum concentrations of lactate dehydrogenase fell, and in two of these patients symptoms improved. We were able to measure BCL-2 levels by flow cytometry in the samples of five patients, two of whom had reduced levels of BCL-2 protein. INTERPRETATION: In patients with relapsing non-Hodgkin lymphoma, BCL-2 antisense therapy led to an improvement in symptoms, objective biochemical and radiological evidence of tumour response, and down-regulation of the BCL-2 protein in some patients. Our findings are encouraging and warrant further investigations of BCL-2 antisense therapy in cancer treatment.