Stephen H. Curry

Why Have So Many Drugs with Stellar Results in Laboratory Stroke Models Failed in Clinical Trials

Abstract: The failure, in the clinic, of at least fourteen potential neuroprotective agents expected to aid in recovery from stroke, after studies in animal models had predicted that they would be successful, is examined in relation to principles of extrapolation of data from animals to humans. Allometric scaling of glutamate data, especially duration of elevated glutamate levels in CSF and plasma, is used to support a hypothesis that treatment needs to be extended for the time that glutamate is elevated in the individual patient. According to this scenario, trials should be restricted to patients with progressing stroke and associated elevated glutamate levels, and patients without elevated glutamate might show adverse effects of drug treatment if normal levels of glutamate, which may be associated with neuroprotection, are antagonized.

Clinical and biochemical comparison of clorazepate and diazepam.

Clorazepate and diazepam were compared with respect to clinical effectiveness and concentrations of benzodiazepine compounds in plasma in 15 severely anxious outpatients. Each patient was studied in a double blind trial incorporating two-week periods of the two drugs and of placebo. The doses were almost equimolar—5 mg diazepam or 7·5 mg clorazepate three times daily. Clinical progress was assessed by visual analogue scales and by the Symptom Rating Test. Psychopathology scores were highest at the end of the placebo periods, and lowest at the end of the clorazepate periods, regardless of the order of treatments. After diazepam, both diazepam and N-desmethyldiazepam (nordiazepam) were detected in blood, and after clorazepate, only N-desmethyldiazepam was detected. N-Desmethyldiazepam concentrations were higher after clorazepate. Clinical progress was apparently related to the concentration of N-desmethyldiazepam in plasma.

Protective effect of dichloroacetate in a rat model of forebrain ischemia

Dichloroacetate (DCA) activates the pyruvate dehydrogenase complex (PDHC), and improves the recovery of cerebral pH, lactate, ATP, and PCr following reperfusion in animal models of forebrain ischemia. In order to determine whether this results in neuroprotection, rats were administered NaDCA (100 mg/kg or 10mg/kg i.v.) 10 min before 12 min of normothermic forebrain ischemia (bilateral carotid artery occlusion plus systemic hypotension, 45 mmHg). Neuronal injury assessed histopathologically 7 days post-ischemia was significantly reduced in the CA1 region of the hippocampus, the dorsal lateral striatum, and the neocortex, in rats treated with 100 mg/kg NaDCA, but not in rats treated with 10 mg/kg NaDCA.

Chromatographic separation of thioridazine sulphoxide and N-oxide diastereoisomers: identification as metabolites in the rat.

(±)‐Thioridazine and (±)‐desmethylthioridazine have been oxidized to produce a number of chiral sulphoxide and amine oxide compounds. Diastereoisomeric isomers were separated by thin‐layer and high performance liquid chromatography. Thioridazine‐5‐sulphoxide, N‐desmethylthioridazine‐5‐sulphoxide and thioridazine‐N‐oxide diastereoisomers were found to be thioridazine metabolites following dosing in rats or after in‐vitro incubation with rat liver homogenate.

On the Relationship Between Plasma Concentrations of Drugs and Outcome of Stroke Studies in Laboratory Animals

Abstract: In assessing plasma concentrations of drugs in relation to neuroprotective effect, emphasis should be placed on measured or calculated concentrations during the window of opportunity for effect, rather than at the end of the experiment. Unbound (plasma free) concentrations should be especially considered as should brain penetration to the stroked area. Problem‐solving exercises should include post hoc assessment of dosing residues and proof of exposure. The shape of the graph of response versus concentration in plasma is very steep, giving the impression of an all‐or‐none effect. Although higher doses lead to greater effects, attempts to statistically correlate plasma level and infarct size are likely to be unsuccessful. There is strong evidence that the pharmacokinetic properties of drugs are affected by the physiological consequences of ischemia.

Benzoic acid is not the only important product of accelerated metabolism of cocaine

Xiabin Chen et al. (1) describe pioneering work with a modified drug-metabolizing enzyme, a butyrylcholinesterase (BChE) analog, intended to prolong BChE activity in humans, hoping that the result would be accelerated cocaine metabolism. This work is exciting to those involved in pharmacokinetic approaches to drug toxicity; such constructs promise to be the first drug-metabolizing enzymes used as therapeutic agents. The analog described (1) seems to be the third of its type; this analog is apparently the longest lasting in the series (2, 3).