1. The structure of the drug d-fenfluramine is shown below. The molecule has a molecular weight of 231 Da and a log P of 3.4.
Figure 1: d-fenfluramine
The increase in plasma prolactin concentration following oral administration of d-fenfluramine was measured in tension-type headache patients and controls. Tension-type headache patients (n=20) and controls (n=20) were evaluated by a neurologist using International Headache Society criteria (IHS) for headache diagnosis, and also by a psychiatrist using DSM V criteria. All subjects were female, drug free and were matched for age and menopausal status. No patient was currently diagnosed as suffering from clinical depression. Subjects fasted from the previous midnight until the end of the experiment. At 8.30am on the day of the study, a baseline blood sample was taken from each patient (table 1). At 9.00am d-fenfluramine (60mg) was given orally, and hourly blood samples taken for the next 5 hours. The blood was centrifuged and the resulting plasma was stored frozen at –20oC. Samples were assayed for prolactin in duplicate, using an enzyme linked immunosorbent assay (ELISA) (table 2).
Table 1: Baseline plasma prolactin concentrations in tension-type headache patients and controls
Subject Baseline plasma prolactin (ng/ml)
Controls (n=20) 12.5 ±3.2
Headache patients (n=20) 13.3 ±4.3
Difference in mean prolactin between controls and headache patients: not significant. Student’s t test.
Table 2: Baseline corrected (T=0) plasma prolactin concentrations in tension-type headache patients and controls following oral fenfluramine administration
Time after administration of fenfluramine (h) Plasma prolactin (ng/ml) (baseline corrected)
Headache Patients (n=20)
1 1.3±0.7 1.5±0.8*
2 2.1±0.9 8.6±2.8**
3 12.0±3.3 25.5±5.7**
4 14.2±3.1 26.8±4.9**
5 13.8±4.7 21.9±3.8**
*Difference in mean prolactin between controls and headache patients: not significant. Student’s t test
**Difference in mean prolactin between controls and headache patients at each time point: p<0.0001. Student’s t test. Headache symptoms were also recorded during the study for both patients and controls at baseline and each hour for the following 5 hours. The IHS headache symptom rating scale of 3 for severe, 2 for moderate, 1 for mild and 0 points for no symptoms was used (table 3). Table 3: Total headache scores in tension-type headache patients and controls in the 5 hour period following oral fenfluramine administration Headache score Controls (n=20) Tension Type Headache Patients (n=20) Baseline score 0.5 ± 0.4 1.1 ± 1.5 Total score over 5h 0.6 ± 1.3 NS 12.5 ± 4.5 * *Difference in mean headache score between baseline and over 5h in headache patients: p<0.00001. Student’s t test. Difference in mean prolactin between baseline and over 5h in controls. NS=Not significant. Student’s t test. The correlation between headache score and plasma prolactin concentration at each time point in tension-type headache patients in the 5 hour period following oral fenfluramine administration was also determined (table 4). Table 4: Correlation between headache score at each time point and plasma prolactin concentration in tension-type headache patients in the 5 hour period following oral fenfluramine administration Headache score Controls (n=20) Tension Type Headache Patients (n=20) Correlation (r) 0.23 NS 0.68* *Correlation between headache score and plasma prolactin concentration: p<0.001. Spearman Rank test. NS =not significant. a) With reference to d-fenfluramine’s characteristics, explain why you would expect the drug to be able to cross the blood brain barrier. (3 marks) b) Explain the purpose of measuring plasma prolactin in the subjects following oral fenfluramine administration. (2 marks) c) Identify three pieces of good experimental practice in the way in which the experiment was conducted. (3 marks) d) Describe the main findings of the study. (6 marks) e) If these results are confirmed by studying larger numbers of headache patients and controls, what could they indicate about the underlying pathology of headache, and the nature of the defect causing these results? (3 marks) f) Suggest experimental work that could be undertaken to investigate your suggestions further. (3 marks) Section B 2. Explain the cause(s) of Parkinson’s disease, and discuss how current and developing treatments may treat this disorder. (20 marks). Section B 3. Answer both parts of the question: (a) Discuss how dopaminergic pathways are involved in the pathophysiology of schizophrenia and therapeutic actions of antipsychotic drugs. Provide experimental/clinical evidence where possible to support your answer. (7 marks) (b) Discuss the symptoms and signs of side effects/adverse effects of 1st generation antipsychotic drugs including the mechanisms by which these effects are caused. (6 marks) (c) Briefly discuss the evidence that supports a protective role of oestrogen against schizophrenia and the therapeutic potential of oestrogen in treatment of schizophrenia. (7 marks) Order Now
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