Marie Blom

The effects of levodopa and haloperidol on flash and pattern ERGs and VEPs in normal humans

We investigated the effects of single doses of the dopamine agonist levodopa and the dopamine antagonist haloperidol on pattern and flash electroretinograms (ERGs) and visual evoked potentials (VEPs) in normal subjects. A placebo and two treatment regimens were administered in a randomized double-masked design. No significant intertreatment differences in the pattern ERGs and VEPs were noted. Although not statistically significant, a clearly discernible tendency was found for increased flash ERG b-wave amplitudes after levodopa administration compared with placebo. In comparison with placebo and levodopa, haloperidol was associated with significantly prolonged flash ERG b-wave implicit times, including each oscillatory potential, which also showed increased duration, particularly in the O1–O3 interpeak implicit time. The failure of pattern ERGs and VEPs to show changes after haloperidol may have been related to the timing of the recordings, which took place during the presumed phase of rising blood levels and before the flash ERG and VEP recordings. Our findings further demonstrated the reliability of the flash ERG in revealing changes in dopaminergic status in the visual system and suggest that steady-state (flicker) ERGs, cone ERGs, and oscillatory potentials have particular use in this regard.

Effects of clobazam and clonazepam on saccadic eye movements and other parameters of psychomotor performance.

SummaryThe effects of two benzodiazepine anti-convulsants clobazam (20 mg) and clonazepam (2 mg) in a variety of psychomotor performance tests were compared in a placebo controlled double-blind acute oral dose study in ten healthy volunteers. Assessments included critical flicker fusion (CFF) threshold, the Sternberg memory scanning and choice reaction time (CRT), peak saccadic velocity (PSV) and visual analogue scales, all previously shown to be sensitive to the effects of benzodiazepines.Clobazam did not significantly impair saccadic eye movements, CFF threshold, Sternberg memory scanning and CRT compared to placebo. Clonazepam significantly lowered PSV, reduced the CFF threshold, slowed the Sternberg CRT and decreased an alertness factor in the visual analogue scales compared to placebo. Clonazepam significantly increased memory scanning time compared to clobazam. Clobazam was remarkably free of cognitive and psychomotor side-effects.

The effects of alprazolam, quazepam and diazepam on saccadic eye movements, parameters of psychomotor function and the EEG

Summary— The effects of a single oral dose of alprazolam (1 mg), quazepam (15 mg) and diazepam (10 mg) on the peak saccadic velocity (PSV) of saccadic eye movements (SEM), the Sternberg memory scanning and choice reaction time (SMS‐CRT), critical flicker fusion frequency (CFFF), spectral analysis of the EEG and a mood scale were assessed in 9 healthy volunteers in a double‐blind, placebo‐controlled crossover study. Alprazolam revealed greater sedative effects than diazepam in the above‐mentioned tests. Quazepam had the least sedative effect of the 3 drugs tested, showed a time lag at the onset of its effects and a more prolonged effect on psychomotor impairment than reported previously.

Effects of single doses of diazepam, chlorpromazine, imipramine and trihexyphenidyl on visual-evoked potentials.

There is increasing evidence that the P 100 peak of the pattern-reversal visual-evoked potential (VEP-PR) is delayed by drug-induced dopamine antagonism and in Parkinsons disease. Recent studies have reported that components of the flash-VEP (VEP-F) are delayed by an anticholinergic which does not affect the VEP-PR. The present study found that a single dose of chlorpromazine increased the latencies of the VEP-PR and of the VEP-F and increased the VEP-F P2 amplitude. Trihexyphenidyl increased the VEP-PR amplitude but had only minor effects on the VEP-F. There was a tendency for imipramine to increase VEP-F latencies, especially the N3 peak, but had no effect on the VEP-PR. Both VEPs were unaffected by diazepam. These VEP findings add further support to the role of dopamine in the human visual system. Possible reasons are advanced for the failure of trihexyphenidyl to cause previously reported VEP changes associated with hyoscine hydrobromide. Several important issues need to be addressed by future research.

Lack of effect of amitriptyline on risperidone pharmacokinetics in schizophrenic patients.

The interaction between plasma concentrations of the tricyclic antidepressant amitriptyline and the metabolism of the new antipsychotic risperidone was studied in 12 patients with chronic schizophrenia. Each patient received 3 mg risperidone twice a day for 28 days. Amitriptyline was coadministered at doses of 50 mg/day on day 15 and 100 mg/day on days 16 to 21. Amitriptyline did not significantly affect the mean plasma concentrations or pharmacokinetics of risperidone in schizophrenic patients or influence the antipsychotic fraction (the total concentration of risperidone and 9-hydroxyrisperidone, its primary and biologically active metabolite). These results suggest that risperidone dose need not be adjusted when coadministered with amitriptyline at doses up to 100 mg/day in schizophrenic patients.

Effects of diclofenac on isradipine pharmacokinetics and platelet aggregation in volunteers.

SummaryIn this open, two-period crossover study in 18 healthy male volunteers, a single oral dose of 50 mg diclofenac was administered alone and on day 7 of multiple oral dosing of 5 mg b.i.d. isradipine to assess a possible pharmacokinetic interaction. The effect of these drugs on ex vivo platelet function was also determined.Serial blood samples were obtained over 12-hour periods on three occasions: after the single diclofenac dose; after the morning dose of isradipine on day 6 and after co-administration of both drugs on day 7 of steady-state isradipine administration. Additional samples were taken at 2 h post dose for determination of ex vivo platelet aggregation. Isradipine plasma concentrations were determined by a gas chromatographic method and diclofenac plasma concentrations by an HPLC method.The pharmacokinetic characteristics of diclofenac were unaltered during co-administration. The maximum plasma concentration of isradipine was increased 19.6% during co-administration from 5.06 to 6.05 ng·ml−1. This is not expected to be of clinical importance. Isradipines apparent total body clearance and steady-state AUC remained unchanged. Ex vivo induced platelet aggregation was not affected by any of the treatments.

The comparison of the effects of multi and single doses of buspirone, chlordiazepoxide and hydroxyzine on psychomotor function and EEG

Summary— This study compares the effects of buspirone (5 mg), chlordiazepoxide (5 mg), hydroxyzine (10 mg) and placebo on psychomotor function and EEG, when taken thrice daily for a period of two weeks, with those after a single dose administration. Nine healthy volunteers participated in the study. The battery of psychomotor tests included peak velocity of saccadic eye movements (SEM), a Sternberg memory scanning and choice reaction time test (SMS‐CRT) and critical flicker fusion frequency (CFFF). The peak velocity of saccadic eye movements was significantly impaired by the single dose of hydroxyzine (P = 0.03) in comparison to the multidose results. A similar comparison regarding buspirone only approached significance (P = 0.07). The SMS‐CRT and CFFF did not reveal any difference between the multi and single dose regimens. Spectral analysis of the EEG did not distinguish between the multi and single dosage schedules regarding the respective drugs in the low doses administered.

Comparative Pharmacology of Salmeterol and Formoterol and their Interaction with Salbutamol in Healthy Volunteers

SummarySalmeterol and formoterol display similar β2 selectivity to salbutamol, but both are more potent than the latter. In vitro studies suggest that salmeterol is a partial β2 agonist. This raises the possibility that salbutamol may not be optimally effective when administered after salmeterol. The published onset of action of salmeterol (17.6 minutes) is slower than formoterol (1.7 minutes) or salbutamol (0.8 minutes). The aim of the present study was to determine the additional effect of salbutamol when preceded by either salmeterol or formoterol. 12 healthy volunteers who responded to a histamine challenge test, participated in a placebo-controlled, single-blind crossover study. Serial dilutions of histamine were inhaled until a 20% decrease in forced expiratory volume in 1 second (FEV1) was obtained [provocation dose (PD)20-FEV1]. The bronchodilators were administered in a randomised way as salmeterol (50µg), formoterol (24µg), salbutamol (200µg) or placebo, and the combination of salmeterol, formoterol or placebo with salbutamol. The combined effect of formoterol- and salbutamol-mediated bronchodilatation differed significantly from the effect of the salmeterol and salbutamol combination (p = 0.01) at 1 minute. However, both combinations caused significant bronchodilatation at 5 minutes (p = 0.002) when compared with placebo. These results suggest that formoterol has a quicker onset of action than salmeterol and that salmeterol seemingly does not interfere with the bronchodilatory action of salbutamol.

The effects of an estradiol transdermal therapeutic system, alone and in combination with naproxen, on urge incontinence in elderly women: a pilot study

The aim of this study was to evaluate the effects of a transdermal estradiol delivery system, alone and in combination with naproxen, in elderly women with confirmed urge incontinence. An open-label, single-blind pilot study was conducted in which an estradiol transdermal therapeutic system (TTS) alone, or combined with naproxen 250-mg tablets twice daily, or placebo TTS were given according to a randomized, crossover design for a period of 8 weeks. Cystometric examination was performed after each medication session. A washout period of 2 weeks followed each medication session. Bladder-diary charts were completed by each patient and evaluated as a subjective measure of that patients symptoms especially with regard to frequency of urination, nocturia, and episodes of incontinence. Sixteen participants completed the study. Estradiol TTS as well as estradiol TTS plus naproxen increased bladder capacity significantly (P < 0.05) when compared with placebo. The volume at which the first urge to void was perceived was increased significantly (P = 0.01) by estradiol TTS plus naproxen compared with placebo. These results suggest that estrogen alleviates urge incontinence.

Effects of Two Anticholinergic Drugs on Electroretinograms and Visual Evoked Potentials in Healthy Human Subjects

A battery of electroretinograms (ERGs) and visual evoked potentials (VEPs) were recorded from 12 normal, male volunteers after the intravenous administration of either biperiden 2.5 mg, atropine 1.5 mg or placebo, at weekly intervals. Self-reports indicated that both drugs caused significantly reduced levels of alertness compared to placebo, but more so with biperiden than atropine. Biperiden was not, however, associated with significant changes to ERGs, while atropine caused a few isolated, significant increases to implicit times. There were no significant treatment effects on pattern ERGs or VEPs. The flash VEP latencies and amplitudes recorded after the anticholinergics did not differ from placebo. These preliminary findings suggest that these anticholinergics do not have marked effects on either ERGs or VEPs.