Elements of informed consent for pharmacogenetic research; perspective of the pharmacogenetics working group.
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Clinical Trials as Topic↗
Biomedical subjects
C Brazell
Publications and source records attributed to C Brazell.
Maximizing the value of medicines by including pharmacogenetic research in drug development and surveillance.
Genetics provides significant opportunities to maximize the safety and efficacy of medicines. Over the next 3--5 years, it may be possible to develop tools that use selective information from patients' DNA to enable healthcare professionals to predict more accurately those patients at risk of serious adverse events to some medicines currently available. This is likely to be followed, over the next 5--10 years, by the application of the technology to predict more accurately if individual patients will obtain a therapeutic benefit from a particular medicine. The ability to accurately predict patient response will inevitably change the way medicines are developed, evaluated, and prescribed. Advances in single nucleotide polymorphism (SNP) map technology are likely to drive this innovation. Abbreviated SNP profiles will provide the means to define medicine response tests, thereby allowing clinicians to select the medicine to which the patient is likely to gain the greatest benefit and least risk. This will help to maximize efficacy and reduce the incidence of drug-related adverse events. It may be possible to identify SNP profiles during larger Phase II clinical trials which predict efficacy, and use these to form the basis of Phase III entry criteria. As a result, Phase III trials may be streamlined for many medicines making them smaller, more efficient, and more focused. In addition it may be possible to incorporate pharmacogenetics into postmarketing surveillance strategies to provide a means to identify SNPs which predict uncommon serious adverse drug reactions, and so refine the initial medicine response test. The ability to develop drugs with a predictable response will allow clinicians to provide targeted treatment for patients, with greater confidence of safety and efficacy. Patients therefore will receive more efficacious, timely, and well-tolerated medicines. The challenge for those involved in drug development is to model and evaluate the application of pharmacogenetics so that steps can be taken to realize this potential.
Cost-Benefit Analysis↗
The dose-response relationship and therapeutic window for dizocilpine (MK-801) in a rat focal ischaemia model.
The purpose of the present study was to examine the dose-response relationship and the maximum time for which effective therapy could be delayed for the N-methyl-D-aspartate antagonist dizocilpine (MK-801) as a neuroprotective agent in a permanent focal ischaemia model in the rat. The ED50 for dizocilpine in the amelioration of cortical damage in this model was found to be approximately 0.3 mg/kg (single i.p. dose, 30 min post onset of ischaemia) and significant protection was only obtained when therapy (3 mg/kg i.p.) was delayed for one hour or less after the onset of ischaemia. In a further experiment, dizocilpine 3 mg/kg i.p., produced a peak plasma level of 44 ng/ml and had a t1/2 elimination of 1.65 h.
Analysis of Variance↗
Reversal of cognitive impairment by heptyl physostigmine, a long-lasting cholinesterase inhibitor, in primates.
Cholinergic replacement therapy for Alzheimer's disease using existing cholinesterase inhibitors is compromised by short duration, meagre benefits restricted to subgroups of patients, and peripheral toxicity. Heptyl physostigmine is a lipophilic carbamate derivative of physostigmine. In rhesus monkeys, heptyl physostigmine (0.2-0.9 mg/kg i.m.) fully reversed a scopolamine-induced cognitive impairment. Following oral administration in squirrel monkeys, heptyl physostigmine (8 mg/kg) induced long-lasting hypothermia (greater than or equal to 4 h), a centrally-mediated cholinergic effect. Erythrocyte acetylcholinesterase activity was inhibited by 86% at the time of peak hypothermia (180 min). Clinical trials with heptyl physostigmine will enable a more rigorous evaluation of cholinomimetic therapy for dementia.
Acetylcholinesterase↗
Plasma and CSF levels of dizocilpine (MK-801) required for neuroprotection in the quinolinate-injected rat striatum.
This study has identified the range of plasma and cerebrospinal fluid (CSF) concentrations of the uncompetitive N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) required for neuroprotection in the quinolinate-lesioned rat striatum. Dizocilpine was given i.v. as a bolus injection followed by a continuous infusion for 4 h, drug administration starting 30 min after a unilateral, intrastriatal injection of 200 nmol quinolinate. Neurodegeneration was assessed 7 days later in striatal homogenates by measuring the activities of the enzymes choline acetyltransferase and glutamate decarboxylase. Stable plasma levels of dizocilpine were achieved over the 4 h of infusion and the drug appeared rapidly in the CSF to reach steady state levels which were approximately 50% of the corresponding plasma values. When the degree of drug bound to plasma and CSF protein (as determined in in vitro experiments with [3H]dizocilpine) was taken into account, the steady state plasma and CSF concentrations were equivalent, indicating free exchange of dizocilpine between these compartments. A small, but significant, neuroprotective effect with respect to both enzyme markers was obtained with free steady state plasma and CSF concentrations of 24 and 21 nM. A high degree of neuroprotection occurred with steady state plasma and CSF concentrations of 47 and 40 nM, respectively, which was not improved by raising the dizocilpine concentration in these compartments further, indicating a maximal effect. The CSF concentrations required for neuroprotection in this model are close to the known affinity of dizocilpine for the N-methyl-D-aspartate receptor as determined in in vitro experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
5-Hydroxytryptamine (5-HT)-induced shape change in human platelets determined by computerized data acquisition: correlation with [125I]-iodoLSD binding at 5-HT2 receptors.
The 5-HT-induced shape change and subsequent aggregation of platelets provides a functional assay for 5-HT2 receptors. In the present study we describe a method to increase aggregometer sensitivity by digital conversion of the voltage produced by changes in light transmittance through a platelet suspension, thereby allowing accurate analyses of the primary shape-change response. The pharmacology of 5-HT-induced shape change was then compared with that of [125I]-iodoLSD binding in human platelets. 5-HT caused a dose-dependent change in platelet shape (maximum response 5 x 10(-6) M, EC50 10(-6) M). Furthermore, there was a significant correlation across a selection of drugs between IC50 values for inhibition of 5-HT-induced shape change and for inhibition of platelet binding of the 5-HT2 receptor ligand [125I]-iodoLSD. These results support the hypothesis that 5-HT-induced shape change and [125I]-iodoLSD binding in human platelets are mediated through the same receptor, and validate the methods of data acquisition described.
Blood Platelets↗
The neuroprotective action of dizocilpine (MK-801) in the rat middle cerebral artery occlusion model of focal ischaemia.
1. An acute model of focal ischaemia, which involves permanent occlusion of the middle cerebral artery of the rat with 4 h survival, was used to find the minimum effective plasma concentration of dizocilpine (MK-801) and to determine its dose-effect relationship. 2. MK-801 was administered at the time of occlusion and was given as an i.v. bolus followed by an infusion for 4 h to maintain a steady state plasma concentration of the drug throughout the study. MK-801 was given at 3 dose levels; 0.04 mg kg-1 i.v. bolus + 0.6 micrograms kg-1 min-1 infusion; 0.12 mg kg-1 i.v. bolus + 1.8 micrograms kg-1 min-1 infusion; 0.4 mg kg-1 i.v. bolus + 6 micrograms kg-1 min-1 infusion, which gave mean plasma levels over the 4 h of 8.0 ng ml-1, 18.9 ng ml-1 and 113.2 ng ml-1 respectively. 3. MK-801 at 8.0 ng ml-1 gave 10% reduction in the volume of ischaemic brain damage in the cerebral cortex which just reached significance. The middle dose of MK-801 (18.9 ng ml-1) gave a highly significant reduction in the volume of ischaemic brain damage in the cerebral cortex and hemisphere, volumes of ischaemic tissue being reduced by 60% and 50% compared to saline-treated animals, respectively. The highest plasma concentration of MK-801 (113.2 ng ml-1) resulted in a 35% reduction in the volume of hemispheric damage and a 40% reduction in the volume of cortical damage, which were significant.4. The reduction in the amount of protection afforded by the highest dose of MK-801 may be due to the hypotensive effect of this dose. There was no protection against the volume of damage in the caudate nucleus for any of the doses of MK-801 tested.5. Therefore the minimum effective plasma concentration of MK-801 was 8.0 ngml1, although the greatest protection was seen with a plasma level of 18.9 ng ml- 1. This correlates well with the concentration of MK-801 required to block N-methyl-D-aspartate (NMDA) receptors and prevent NMDA receptor mediated neurotoxicity in vitro.
Animals↗
5HT2 receptor changes in rat cortex and platelets following chronic ritanserin and clorgyline administration.
Chronic administration of clorgyline or ritanserin to adult rats for 28 days followed by a 3 day drug-free period results in a significant decrease in 5HT2 receptor number (Bmax) in rat frontal cortex from 315.23 +/- 10.72 fmol/mg protein to 249.63 +/- 13.99 fmol/mg protein and 222.55 +/- 17.17 fmol/mg protein, respectively. On rat blood platelets, ritanserin significantly increases recept number from 26.18 +/- 3.83 fmol/mg protein to 50.94 +/- 7.96 fmol bound/mg protein, whereas clorgyline has no significant effect (21.32 +/- 4.78 fmol/mg protein). Following both drug regimens, the affinity (Kd) of the respective ligands for the receptor is not significantly different from controls: the mean Kd value of the three groups for [3H]ketanserin is 1.57 +/- 0.05 nM in cortex and 0.83 +/- 0.25 nM for [125I]iodolysergic acid diethylamide (LSD) on platelets. Clorgyline increases serotonin (5HT) and noradrenaline (NA) levels in cerebellum, and decreases 5-hydroxyindole acetic acid (5HIAA) and homovanillic acid (HVA): ritanserin does not change the levels of the amines or their metabolites. The data shows that platelet and brain changes are not comparable after ritanserin administration. The receptor binding data demonstrates that curve fitting to two data points provides information which is comparable to and as statistically robust as that obtained from eight point saturation curves. Thus, if pilot studies show that the data follows a rectangular hyperbola, two point assays (optimal at 0.1 Kd and 3 Kd) can be used to obtain estimates of Bmax and Kd.
Animals↗
MK-212 increases rat plasma ACTH concentration by activation of the 5-HT1C receptor subtype.
The effects of the serotonin agonist MK-212, on rat plasma ACTH were examined. MK-212 significantly increased plasma ACTH levels, and this effect was blocked by the 5-HT1C antagonists mesulergine and metergoline but not by spiperone, ketanserin, or (-)-pindolol. The results suggest that MK-212 activates the 5-HT1C receptor subtype to increase ACTH.
Adrenocorticotropic Hormone↗
Hallucinogenic drugs are partial agonists of the human platelet shape change response: a physiological model of the 5-HT2 receptor.
We have assayed several phenylalkylamine and indolealkylamine hallucinogens, as well as structurally similar nonhallucinogens, for their effect on human platelet shape change, a physiological model for the central serotonergic 5-HT2 receptor. The hallucinogenic drugs lysergic acid diethylamide (LSD-25), N,N-dimethyltryptamine (N,N-DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), 4-iodo-2,5-dimethoxyphenylisopropylamine (DOI), bufotenine, and mescaline all showed a characteristic 5-HT2 partial agonist effect on platelet shape change. Nonhallucinogens with structural similarity to hallucinogens did not share this profile. Lisuride, methysergide, and lysergic acid showed antagonism of 5-HT-induced shape change, but none were shape change agonists. Other "psychoactive" or mood-altering drugs (cocaine, amphetamine, phencyclidine) showed poor antagonism of 5-HT-induced platelet shape change. This work refines recent ideas that some of the behavioral effects of LSD-type hallucinogens in humans are due to their actions at 5-HT2 receptors and suggests that these hallucinogens are partial 5-HT2 agonists.
Blood Platelets↗
Activation of the 5-HT1A receptor subtype increases rat plasma ACTH concentration.
Serotonergic (5-HT) neuronal pathways regulate the release of adrenocorticotropin hormone (ACTH) from the pituitary gland probably through the action of hypothalamic corticotropin-releasing hormone (CRH). 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist, dose dependently (0.016-3 mg/kg s.c.) increased rat plasma ACTH concentration. This response was blocked stereoselectively by (-)-pindolol, known to have 5-HT1 antagonist properties, but not by (+)-pindolol, beta 1-, beta 2- or alpha 1-adrenoceptor, dopamine, muscarinic, 5-HT2 or 5-HT3 receptor antagonists. Similar increases of plasma ACTH were induced by other 5-HT1A receptor ligands (buspirone, ipsapirone and gepirone). These results suggest that activation of the 5-HT1A receptor induces the secretion of ACTH from the rat pituitary gland.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Relationship of increased food intake and plasma ACTH levels to 5-HT1A receptor activation in rats.
Various putative agonists of the 5-HT1A receptor subtype induce feeding in rats, probably by activating raphé somatodendritic 5-HT autoreceptors. These drugs also produce a marked increase in plasma concentrations of corticotropin (ACTH). In the present experiment we attempted to localize the site of action of 5-HT1A agonists on the secretion of ACTH and examined the relationship between 5-HT1A agonist-induced feeding and ACTH secretion. Rats were injected with either the high affinity 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.016-1.0 mg/kg, s.c.) or the novel anxiolytics buspirone, gepirone or ipsapirone (2.0-16.0 mg/kg, s.c.), and either had their food intake measured 2 hr post injection or were sacrificed 30-40 min post injection for measurement of plasma ACTH. Plasma ACTH also was measured in rats pretreated with the serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) for three days (150 mg/kg, i.p. per day) and subsequently injected with 8-OH-DPAT (0.3 mg/kg, s.c.). As previously reported, the 5-HT1A agonists increased both food agonists increased both food intake and plasma ACTH concentrations. After 8-OH-DPAT, ipsapirone and gepirone the amount of food consumed was positively correlated with the concentration of plasma ACTH. No such correlation was evident following buspirone. PCPA pretreatment resulted in near total depletion of brain 5-HT content but had no effect on the ACTH rise induced by 8-OH-DPAT. Therefore, in contrast to the presynaptic site previously proposed for 5-HT1A agonist-induced feeding, the present results suggest a agonist-induced feeding, the present results suggest a postsynaptic location for the 5-HT1A receptor mediating ACTH release.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Pharmacogenomics and regulatory decision making: an international perspective.
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Biomarkers↗
Administration of aerosol pentamidine: a program design.
Aerosol pentamidine (AP) is an FDA-approved prophylaxis against pneumocystis carinii pneumonia (PCP) in HIV-infected individuals who have a CD4+ lymphocyte count less than 200/mm3, constitutional symptoms, or a previous history of the pneumonia. The University of Washington Medical Center, a 450-bed tertiary care center, established a successful aerosol pentamidine treatment program, providing treatment in its special procedure nit. The authors present an overview of AP and discuss the role of interdisciplinary teamwork, staff training, patient teaching, and the provision of safety measures for patients and healthcare providers.
AIDS-Related Opportunistic Infections↗