Problem gamblers exhibit reward hypersensitivity in medial frontal cortex during gambling.

Problem gambling (PG) is increasingly conceptualized as an addiction akin to substance abuse, rather than an impulse control disorder, however the mechanism of addiction remains unclear. Neuroimaging investigations have supported a "reward deficiency" hypothesis for PG by suggesting a blunted response to gambling, particularly in the striatum. Here we describe electrophysiological evidence of a hypersensitive response to gambling feedback in problem gamblers. Previous research in healthy participants has shown that feedback during gambling tasks triggers stereotypical neural responses including the Feedback-Related Mediofrontal Negativity (FRN), the feedback-related P300, and an increase in induced theta-band (4-8 Hz) power. We tested the theory that abnormal feedback processing characterizes brain activity in problem gamblers while gambling. EEG was recorded from non-gamblers and self-identified gamblers as they engaged in a computerized version of the Iowa Gambling Task. Feedback about valence (win vs. loss) triggered a FRN in both groups, but in gamblers this was preceded by an early-latency hypersensitive fronto-central difference to feedback. This early FRN was correlated with gambling severity and was localized to medial frontal cortex using distributed source imaging (CLARA). Gamblers also differed in responses to risk, showing a blunted P300 component and less EEG power in the theta band. Here we suggest that a more nuanced interpretation of reward deficiency is called for with respect to PG. For certain aspects of brain function, gamblers may exhibit hypersensitivity to reward feedback more akin to drug sensitization than reward deficiency. Our results also suggest that the neurologically normal brain employs dissociable systems in the processing of feedback from tasks involving risky decision making.

Sumatriptan clinical pharmacokinetics.

Sumatriptan is a novel serotonin 1 (5-hydroxytryptamine 1; 5-HT1)-like agonist which has been shown to be effective in the treatment of acute migraine. Single-dose pharmacokinetic studies reflect the way that sumatriptan will be used in routine practice, but relatively few studies have been published. Bioavailability is high (96%) following subcutaneous injection, but low (14%) following oral administration because of first-pass metabolism. Absorption is rapid after subcutaneous injection, with peak concentration reached in 10 minutes. After oral administration, multiple peak concentrations are observed, but a concentration that is 75% of the final peak concentration is usually reached within 45 minutes. Less than 20% of the drug is protein bound. The volume of distribution is greater than total body water at 170L. Total plasma clearance is rapid, with an elimination half-life of around 2 hours. There is one major metabolite (an indole acetic acid analogue) which is excreted in the urine as the free acid and its ester glucuronide conjugate. The pharmacokinetic profile of sumatriptan is not significantly affected by an acute migraine attack (absorption phase), old age or gender. Pharmacokinetic studies in individuals with hepatic and renal disease have not been published; however, care should be taken when sumatriptan is administered to patients with liver disease until such information is available. No significant interaction was found between sumatriptan and propranolol, flunarizine, pizotifen or alcohol (ethanol).

Stereoisomers and drug toxicity. The value of single stereoisomer therapy.

All drugs produce adverse effects, though the risk varies widely between different compounds. Many toxic reactions are an extension of the mechanism responsible for the therapeutic effect and can be avoided by careful dose adjustment. Other adverse events are not related to the beneficial action of the drug. Recent interest has focused on the role of the different properties of individual drug enantiomers in causing drug toxicity. For drugs with a single chiral centre, both enantiomers may be therapeutically active. However, if the main therapeutic benefit is in only 1 enantiomer, several possibilities exist for the other enantiomer--inactive, a qualitatively different effect, an antagonistic effect or greater toxicity.

The use of cimetidine to reduce dapsone-dependent methaemoglobinaemia in dermatitis herpetiformis patients.

1. We have attempted to reduce dapsone-dependent methaemoglobinaemia formation in six dermatitis herpetiformis patients stabilised on dapsone by the co-administration of cimetidine. 2. In comparison with control, i.e. dapsone alone, methaemoglobinaemia due to dapsone fell by 27.3 +/- 6.7% and 26.6 +/- 5.6% the first and second weeks after commencement of cimetidine administration. The normally cyanotic appearance of the patient on the highest dose of dapsone (350 mg day-1), underwent marked improvement. 3. There was a significant increase in the trough plasma concentration of dapsone (2.8 +/- 0.8 x 10(-5)% dose ml-1) at day 21 in the presence of cimetidine compared with control (day 7, 1.9 +/- 0.6 x 10(-5)% dose ml-1, P less than 0.01). During the period of the study, dapsone-mediated control of the dermatitis herpetiformis in all six patients was unchanged. 4. Trough plasma concentrations of monoacetyl dapsone were significantly increased (P less than 0.05) at day 21 (1.9 +/- 1.0 x 10(-5)% dose ml-1) compared with day 7 (1.6 +/- 0.9 x 10(-5)% dose ml-1:control). 5. Over a 12 h period, 20.6 +/- 8.9% (day 0) of a dose of dapsone was detectable in urine as dapsone hydroxylamine. Significantly less dapsone hydroxylamine was recovered from urine at day 14 (15.0 +/- 8.4) in the presence of cimetidine, compared with day 0 (control: P less than 0.05). 6. The co-administration of cimetidine may be of value in increasing patient tolerance to dapsone, a widely used, effective, but comparatively toxic drug.

Dihydroergotamine: a review of its use in the treatment of migraine and other headaches.

Dihydroergotamine has been one of the main drugs used in the treatment of migraine for greater than 40 years. The recent introduction of the more selective 5-HT antagonist sumatriptan will challenge the place of dihydroergotamine in migraine therapy and indicates the need to review the evidence for the use of dihydroergotamine. Although there is little evidence from double-blind clinical trials, dihydroergotamine does appear to be effective in the treatment of acute attacks and in the prevention of migraine. Its place in treatment is in cases where simple analgesics alone or in combination with other agents fail to provide relief. Further studies are necessary to compare dihydroergotamine with sumatriptan for acute migraine and with beta-blockers in prophylaxis to determine its future role in migraine therapy.

Sumatriptan and cerebral perfusion in healthy volunteers.

1. The effect of sumatriptan on regional cerebral perfusion was studied in healthy volunteers. 2. Intravenous sumatriptan (2 mg) had no detectable effect on regional cerebral perfusion as measured using a SPECT system with 99technetiumm labelled hexemethylpropyleneamineoxime. 3. Sumatriptan had no effect on pulse, blood pressure or ECG indices. 4. All six volunteers experienced minor adverse effects during the intravenous infusion.

Lack of an interaction between propranolol and sumatriptan.

1. The effect of twice-daily dosing with propranolol on the pharmacokinetics and pharmacodynamics of a single oral dose of sumatriptan was investigated in 10 healthy male subjects. 2. Each subject received 7 days dosing with propranolol (80 mg twice daily) plus a single dose of sumatriptan (300 mg orally) on day 7; on another separate occasion, placebo was administered for 7 days plus a single dose of sumatriptan on day 7. There was at least a 7 day washout interval between the two periods of dosing. Pulse and blood pressure were measured up to 10 h after dosing with sumatriptan and blood samples were taken up to 26 h post-dose. 3. Propranolol had no significant effect on any of the derived pharmacokinetic parameters of sumatriptan. The appropriate average parameter values in the presence of propranolol were, respectively: Cmax (120 ng ml-1 vs 126 ng ml-1), tmax (4.5 h vs 3.0 h), AUC (580 ng ml-1 h vs 566 ng ml-1 h), t 1/2,z (1.9 h vs 1.8 h). 4. Propranolol had no significant effect on the pharmacodynamics of sumatriptan, as measured by pulse rate and blood pressure. 5. The results of this study would suggest that no alteration in the sumatriptan dosage will be necessary for migraine patients taking propranolol prophylactic therapy.

Interaction of metoprolol with lorazepam and bromazepam.

The interaction between metoprolol and bromazepam and lorazepam was studied in 12 healthy male volunteers aged 21-37 years. Metoprolol had no significant effect on the pharmacokinetics of bromazepam or lorazepam. However, bromazepam AUC was 35% higher in the presence of metoprolol. Bromazepam enhanced the effect of metoprolol on systolic blood pressure but not on diastolic blood pressure or pulse rate. Lorazepam had no effect on either blood pressure or pulse. Metoprolol did not enhance the effect of bromazepam on the psychomotor tests used in this study. Metoprolol caused a small increase in critical flicker fusion threshold with lorazepam but had no effect on the other tests. Lorazepam (2 mg) was more potent than bromazepam (6 mg) in the doses used in this study. The interaction of metoprolol with bromazepam and lorazepam is unlikely to be of clinical significance. No change in dose is necessary when using these drugs together.

The use of cimetidine as a selective inhibitor of dapsone N-hydroxylation in man.

1. The N-hydroxylation of dapsone is thought to be responsible for the methaemoglobinaemia and haemolysis associated with this drug. We wished to investigate the effect of concurrent administration of cimetidine (400 mg three times per day) on the disposition of a single dose (100 mg) of dapsone in seven healthy volunteers in order to inhibit selectively N-hydroxylation. 2. The AUC of dapsone (31.0 +/- 7.2 micrograms ml-1 h) was significantly increased (P less than 0.001) in the presence of cimetidine (43.3 +/- 8.8 micrograms ml-1 h). 3. Peak methaemoglobin levels observed after dapsone administration (2.5 +/- 0.6%) were significantly (P less than 0.05) reduced in the presence of cimetidine (0.98 +/- 0.35%). 4. The percentage of the dose excreted in urine as the glucuronide of dapsone hydroxylamine was significantly (P less than 0.05) reduced in the presence of cimetidine (34.2 +/- 9.3 vs 23.1 +/- 4.2%). 5. Concurrent cimetidine therapy might reduce some of the haematological side-effects of dapsone.

The measurement of blood pressure: sitting or supine, once or twice?

In 166 patients attending a hypertension review clinic, we compared supine and sitting blood pressure measurements and first and second measurements (1 min apart) in each position to determine whether any differences seen might have implications for the routine measurement of blood pressure in these patients, as a group or as individuals. Measurements were made with the Copal UA-251 semi-automated sphygmomanometer. In the group there was no significant difference between the first and the second diastolic measurements. The first systolic measurement was on average 3-4 mmHg higher than the second in both positions. Mean supine systolic pressures were 2-3 mmHg higher and diastolic pressures 2-3 mmHg lower than the corresponding sitting pressures. In individual subjects there were substantial disagreements between successive measurements in both positions and between positions. However, these differences would not have influenced blood pressure management in more than a few instances. We suggest that two measurements should routinely be taken, and the average recorded, particularly when the average exceeds 155/90 mmHg.

Pharmacokinetics of epanolol after acute and chronic oral dosing in elderly patients with stable angina pectoris.

1. Epanolol is a novel anti-anginal agent which is a beta 1-adrenoceptor partial agonist exhibiting selective beta 1-adrenoceptor antagonist and selective beta 1-adrenoceptor agonist activity. It is mainly metabolised to conjugates prior to excretion in urine and it was of interest to determine if any accumulation occurred in elderly patients. 2. The pharmacokinetics of epanolol have been studied over 72 h after a single oral dose of 200 mg and then over 24 h after 12 consecutive daily oral doses in 13 elderly patients with stable angina pectoris. 3. The peak plasma concentrations (mean +/- s.d.) after the single dose (25.7 +/- 17.0 ng ml-1) were not significantly different (P = 0.35) from those at steady state (32.4 +/- 20.9 ng ml-1). There was wide inter-individual variation on both occasions. The time to peak did not alter significantly during the study with mean values of 1.5 and 1.2 h on acute and chronic dosing respectively. 4. Plasma concentrations declined biphasically with a mean terminal phase half-life of 17 h and 5 fold inter-individual variation. 5. The mean area under the curve to 24 h was not significantly different (P = 0.26) after the single dose (59.0 +/- 29.8 ng ml-1 h) from that at steady state (78.4 +/- 55.0 ng ml-1 h). There was also wide inter-individual variation in these values. 6. In conclusion, the lack of significant accumulation of epanolol indicates that no alteration of dose is necessary when using epanolol in elderly patients with normal renal and hepatic function.

The bioavailability of a mixed micellar preparation of vitamin K1, and its procoagulant effect in anticoagulated rabbits.

We have investigated the pharmacokinetics and procoagulant activity of a new, mixed-micellar preparation of vitamin K1 (MM-K) in male New Zealand White rabbits. Oral administration of MM-K alone caused a significant (P less than 0.01) increase in the plasma concentrations of vitamin K1 as measured by normal-phase high-performance liquid chromatography (HPLC). Maximum plasma concentrations of vitamin K1 (450 ng mL-1, range 133-824 ng mL-1) were recorded at 3.3 h (range 3-5 h), and were significantly (P less than 0.05) greater than those seen after administration of an existing polyethoxylated castor oil preparation (PE-K; Konakion), which were 260 ng mL-1, range 198-390 ng mL-1 (tmax 0.8 h, range 0.4-1.2 h). AUC after MM-K (4.6 micrograms mL-1 h-1, range 2.1-6.3 micrograms ML-1 h-1) was also significantly (P less than 0.05) greater than after PE-K (1.6 micrograms mL-1 h-1, range 1.0-2.1 micrograms ML-1 h-1). However, the bioavailability of vitamin K1 after administration of MM-K was poor (9.4%), and there was considerable intra-individual variability between the concentrations of vitamin K1 recorded in the plasma samples. Both preparations of vitamin K1 stimulated clotting factor synthesis in rabbits anticoagulated with the potent and long-acting coumarin, brodifacoum. Maximum stimulation of clotting factor synthesis by vitamin K1 after MM-K was 87%, range 44-124% (%PCA). The maximum was seen later (tmax 12 h) than after PE-K (PCA 82%, range 47-125%; tmax 5 h). However, there was considerable intra-individual variability in response to both MM-K and PE-K.(ABSTRACT TRUNCATED AT 250 WORDS)

Does a selective 5-hydroxytryptamine antagonist (ICI 169, 369) lower blood pressure in hypertensive patients?

1. The effect of single doses (10, 30 and 50 mg) of a selective 5-HT2 receptor antagonist, ICI 169, 369, on blood pressure, heart rate and the electrocardiogram was studied using a double-blind, placebo-controlled, within subject design in hypertensive patients. 2. ICI 169, 369 did not reduce blood pressure or increase QT interval as has been reported with ketanserin. This suggests that it is the other properties of ketanserin which are responsible for its antihypertensive effect. 3. Plasma concentrations of AUC for ICI 169, 369 were low. This is consistent with low bioavailability due to extensive first pass metabolism. 4. ICI 169, 369 was well tolerated and none of the symptoms reported by the patients was thought to be drug related.

The effect of age and cardiac failure on xamoterol pharmacokinetics.

1. Xamoterol is a cardioselective beta-adrenoceptor partial agonist which may have a role in the management of cardiac failure. Excretion is mainly by the renal route. 2. The kinetics of a single 200 mg oral dose of xamoterol were studied in eight elderly (age 67-82 years) volunteers, eight young (age 21-43 years) volunteers; eight patients with mild to moderate cardiac failure and eight age and sex matched controls. 3. Elderly volunteers had a significantly longer time to reach peak concentration (mean +/- s.e. mean 2.1 +/- 0.2 vs 1.1 +/- 0.1 h) and elimination half-life time (27.0 +/- 2.8 vs 16.4 +/- 3.1 h) compared with young volunteers. The renal clearance of xamoterol was lower in the elderly (115 +/- 12 vs 185 +/- 19 ml min-1) and showed a significant correlation with creatinine clearance (r = 0.85, P less than 0.001). 4. There was no significant difference in any of the pharmacokinetic parameters measured in patients with cardiac failure compared with healthy age and sex matched controls. 5. These results suggest that the maintenance dose of xamoterol could be reduced in elderly patients in relation to impairment of renal function.

Once-daily amlodipine in the treatment of mild to moderate hypertension.

The antihypertensive efficacy of once-daily amlodipine was studied in a group of 30 patients with mild to moderate hypertension in a double-blind, placebo-controlled, parallel-group study. The dose range of amlodipine was 2.5-10.0 mg daily adjusted every 2 weeks for a total treatment period of 8 weeks. Amlodipine produced a significant reduction in blood pressure compared with placebo, the mean difference between baseline and 8 weeks (corrected for placebo effect) being 16/12 mm Hg supine, 14/4 mm Hg standing. Blood pressure returned to baseline values during a terminal 4-week washout period with placebo. There were no significant effects on heart rate. Two patients experienced slight ankle edema while receiving amlodipine 10.0 mg daily but the active drug was otherwise well tolerated.

Once daily amlodipine in the treatment of mild to moderate hypertension.

1. The antihypertensive efficacy of once-daily amlodipine was studied in a group of 30 patients with mild to moderate hypertension in a double-blind, placebo controlled parallel group study. The dose range of amlodipine was 2.5-10 mg daily titrated at 2 weekly intervals for a total treatment period of 8 weeks. 2. Amlodipine produced a significant reduction in blood pressure compared with placebo, the mean difference between baseline and 8 weeks (corrected for placebo effect) being 16/12 mm Hg supine, 14/4 mm Hg standing. 3. Blood pressure returned to baseline values during a terminal 4 week washout period on placebo. 4. There were no significant effects on heart rate. 5. Two patients experienced slight ankle oedema while receiving amlodipine 10 mg daily but the active drug was otherwise well tolerated. 6. Plasma concentration of amlodipine, sampled 24 h after the preceding dose, increased as the dose titration sequence was followed, averaging 2.5 ng ml-1 on 2.5 mg, 4.9 ng ml-1 on 5 mg and 10.5 ng ml-1 on 10 mg.

Sorbinil pharmacokinetics in male and female elderly volunteers.

Sorbinil pharmacokinetics were studied, following a single oral dose, in eight male and eight female healthy, elderly volunteers. Elimination half-life tended to be longer in males than in females. There was no sex difference in AUC or renal clearance. The long elimination half-life of sorbinil in the elderly suggests that accumulation is likely to occur with chronic dosing.