Biomedical subjects
B J Harding
Publications and source records attributed to B J Harding.
The nature of PDQ.
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Deficiency of glutamate dehydrogenase in postmortem brain samples from parkinsonian putamen.
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A strategy for the development of two clinically active cisplatin analogs: CBDCA and CHIP.
The antitumor agent cisplatin has a broad antitumor spectrum and has been incorporated into regimens that are curative for some malignant diseases. However, one of the major limitations to its clinical usefulness is the incidence of severe toxicities involving several major organ systems. Therefore, much enthusiasm has been generated for the development of cisplatin analogs that demonstrate an improved therapeutic index in some preclinical models. The two most promising analogs are CBDCA (carboplatin) and CHIP (iproplatin). The preclinical and early clinical trial results have demonstrated that these two compounds show activity in cisplatin-responsive tumors. The preclinical background providing the rationale for the clinical development of these two analogs is described. We suggest a means of screening for each analog's clinical antitumor activity and determining the analogs' utility against specific malignant diseases compared with that of the parent compound or standard treatment.
Studies of transketolase abnormality in Alzheimer's disease.
The partially purified transketolase from each of eight well-nourished patients with Alzheimer's disease contained significantly less heat-stable component with a significantly longer half-life of heat inactivation than that from eight controls. Immunochemical studies utilizing antibodies to the purified human liver transketolase did not distinguish between red blood cell transketolases of patients with Alzheimer's disease and those of controls. However, three brains from patients with Alzheimer's disease that were deficient in transketolase activity lacked a 69-kilodalton form on immunoblots. Subtle structural abnormalities of transketolase appear to occur in a high proportion of patients with Alzheimer's disease.
Mitochondrial enzymes in hereditary ataxias.
As a test of the hypothesis that mitochondrial abnormalities are common in patients with hereditary ataxias, the activities of two mitochondrial enzymes were studied in platelets from an unselected series of patients. For the group of ataxics, the activity of the pyruvate dehydrogenase complex (PDHC) was 68% of the control (P less than 0.01) and that of glutamate dehydrogenase (GDH) was 81% of the control (P less than 0.05). Of the ataxics studied, 30% had activities of either or both mitochondrial enzymes more than 2 SD below the control mean. Immunoblots of PDHC revealed antibody cross-reacting material in platelets and fibroblasts very similar to those in human brain and appeared normal in platelets from patients with ataxias. Immunoblots of GDH showed a single antibody cross-reacting material in brain but at least two species in normal fibroblasts and platelets. The pathophysiology of hereditary ataxias may often involve mitochondrial damage associated with secondary decreases in the activities of mitochondrial enzymes.
Hexamethylmelamine: a critical review of an active drug.
Hexamethylmelamine is an s-triazine that began clinical trials during the 1960s based on its level of antitumor activity in murine tumor models. Phase I studies were performed using an oral formulation given in divided doses for varying numbers of days. The most frequently reported toxicities included nausea, vomiting, abdominal cramps, anorexia, weight loss and malaise. Less frequently reported toxicities were anemia, thrombocytopenia, leucopenia and peripheral neuropathy. Clinical antitumor activity was noted in the phase I studies in a variety of tumor types. Since then a large number of studies have been performed using hexamethylmelamine as a single agent and in a variety of combinations. Unfortunately, almost none of these studies sought to define the utility of this drug relative to other treatments for the diseases in which it showed activity, or to define the contribution of this drug to the activity of any given combination. Thus its role in the treatment of patients with malignancies remains undefined.