PubMed · 15630130
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P Brook. 2005. Testing for diabetes.. https://doi.org/10.1192/bjp.186.1.78-a
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We investigated simultaneous determination of haloperidol (HAL), its three metabolites [reduced HAL (R-HAL), 3-(4-fluorobenzoyl)propionic acid (FBPA) and 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP)] and two related compounds [spiperone (SPI) and droperidol (DRO)] in phosphate-buffered saline using high-performance liquid chromatography (HPLC) coupled with dual ultraviolet detection (220 and 250 nm). Retention times of HAL, R-HAL, FBPA, CPHP, SPI and DRO were 16.8, 11.8, 10.2, 4.1, 12.6 and 8.3 min, respectively. Their lower limits of detection were 7.5, 14, 4.5, 12, 10 and 20 ng/mL in the same order. The coefficients of variation for their intra- and inter-day assays were less than 7.8 and 9.4%, respectively. Of the other centrally acting drugs, only amoxapine interfered with the peak of DRO. Using our procedure, the binding study of tested compounds to synthetic melanin, human serum albumin and alpha1-acid glycoprotein was performed by determining the unbound concentration to total concentration ratio. These results indicated that simultaneous assay of HAL, R-HAL, FBPA, CPHP, SPI and DRO in phosphate-buffered saline by HPLC equipped with dual ultraviolet detection is simple, sensitive and reproducible. Also, our assay system can be applied to the binding study of these compounds to synthetic melanin, human serum albumin and alpha1-acid glycoprotein.
Prolongation of myocardial repolarisation, i.e. lengthening of the QT interval on surface electrocardiogram, has been recognised as a side effect of many drugs, including antipsychotics. In predisposed individuals, abnormal excessive QT prolongation and severe ventricular arrhythmias (the ventricular tachycardia type 'torsade de pointes', or TdP) may occur. In almost all cases, additional factors are present that increase the propensity of patients to develop TdP, such as serum hypokalemia, the combination of drugs prolonging repolarisation, overdosing, intoxication, and factors interfering with drug metabolism and excretion. Serum hypokalemia and/or bradycardia may induce TdP alone, in the absence of drugs prolonging the QT interval. Experimental studies demonstrate that prolongation of myocardial repolarisation is a class effect of neuroleptics. Clinically, the extent to which individual drugs prolong the QT interval varies. Among the antipsychotics, thioridazine has the greatest propensity to induce abnormal QT prolongations and TdP. Case reports of TdP with other antipsychotics have been published. Physicians prescribing physicians these drugs must be aware that they can induce proarrhythmia in individual cases. They should also be aware of the circumstances which are necessary for abnormal QT prolongation and TdP to develop. Patients should be monitored with regard to these risk factors before and during drug treatment.
How does an excess in a neurochemical lead someone to being paranoid about the intentions of their neighbour? And why does blocking a dopamine receptor improve this symptom? In this article we present a heuristic framework which attempts to link the biology, phenomenology and pharmacology of psychosis. Focussing on dopamine's role in reward prediction and motivational salience we propose that psychosis arises from an aberrant assignment of novelty and salience to objects and associations. Antipsychotics block dopamine receptors and decrease dopamine transmission, which leads to the attenuation of aberrant novelty and salience. This 'salience' framework accounts for existing data and questions several current assumptions about the speed of onset phenomenological effects of antipsychotics and their behavioral effects in animal models. We review new data to show that in contrast to the prevailing idea of a "delayed onset" of antipsychotic action, the improvement is evident in the first few days. Antipsychotics do not eradicate symptoms, but create a state of "detachment" from them. And the actions of antipsychotics in the conditioned avoidance response model, one of the best established animal models for identifying antipsychotic action, are consistent with the idea that they dampen aberrant as well as normal motivational salience. The article discusses the caveats, limitations as well as the clinical implications of the salience framework.