K. De Sommers

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.

Effects of calcitriol on eosinophil activity and antibody responses in patients with schistosomiasis

AbstractObjective: Parasitic infestations are known to elicit T-helper lymphocyte type 2 (Th-2) reactions, characterized by a pronounced eosinophila and high IgE levels. In humans both elevated specific IgE levels and eosinophil counts are associated with resistance to reinfection with schistosomiasis. This study aimed to establish whether the Th-2 reaction could be enhanced with calcitriol (vitamin D3). Calcitriol has been shown to cause a shift from Th-1 to Th-2 type reactions when applied locally to the skin. Methods: Fifty-nine patients with Schistostomahaematobium infection were randomized to one of four treatment modalities, i.e. (a) praziquantel (PZQ) 60 mg · kg−1orally on day 1, (b) PZQ 60 mg · kg−1 on day 1 plus calcitriol 1 μg per day orally for 5 consecutive days, (c) calcitriol 1 μg per day for 5 consecutive days or (d) placebo. Blood for differential counts, eosinophil cationic protein (ECP), specific IgE and IgG to whole-worm antigen, as well as urine samples for egg counts, were collected on days 0 and 21. Results: Baseline values did not differ significantly between the groups. Calcitriol alone resulted in significant increases in circulating lymphocytes (median increase of 5.5%) and the percentage of eosinophil vacuolization (mean increase 28%). It, however, significantly decreased ECP levels (mean decrease 46%). PZQ in combination with calcitriol significantly enhanced production of specific IgE (mean increase 213%) and IgG (mean increase of 170%) and tended to increase eosinophil vacuolization (mean increase 22%). All these changes also differed significantly from those in the placebo group. The specific IgE and IgG levels were also significantly higher than the already increased levels seen with PZQ treatment only. ECP levels were, however, not significantly affected by combination therapy, whereas PZQ alone significantly enhanced ECP production (mean increase 93%). Conclusions: The increases in specific IgE responses and percentage of eosinophil vacuolization favour a Th-2 type of reaction. The ECP values viewed in isolation may, paradoxically, indicate a Th-1 response; this could, however, have been an artefact due to the method of ECP detection ex vivo. Finally, it would seem that calcitriol does cause some immune augmentation when combined with PZQ therapy in patients with schistosomiasis. However, long-term follow-up is needed to prove that these findings would translate into resistance against reinfection.

Effect of cetirizine, ketotifen and chlorpheniramine on the dynamics of the cutaneous hypersensitivity reaction: a comparative study.

SummaryAllergic cutaneous challenge causes mast cell and basophil mediator release which recruit inflammatory cells to the site of antigen administration. This secondary cell infiltration and mediator release is responsible for the changes seen during the late phase of allergic diseases.In this randomised, double-blind, cross-over, placebo controlled study, it was demonstrated that, at steady-state drug concentrations, chlorpheniramine reduced the wheal-and-flare reaction by about 50% compared to the 75% reduction, on average, by cetirizine and ketotifen. Cetirizine significantly reduced eosinophil vacuolisation at all observation periods, i. e. 2, 6, 10 and 24 h, and also inhibited basophil accumulation significantly at 10 h (75% reduction), while chlorpheniramine had a negligable effect on these variables.These changes would indicate that the late phase reaction was modified, especially as eosinophil vacuolisation is known to correlate with late phase intensity, T-lymphocyte infiltration and subsequent tissue damage. It further supports previous speculation that cetirizine inhibit late histamine release by acting on basophils. The extent of induration in the late phase reaction did not differ significantly among the three treatments.Cetirizine and ketotifen, noticeably although not significantly, reduced eosinophil and lymphocyte recruitment. As these two antihistamines differ structurally and in regard to receptor specificity, it is possible that they exert their actions on other, unspecified, receptors.

Possible mechanisms of anti-cholinergic drug-induced bradycardia

SummaryAtropine-induced bradycardia is traditionally ascribed to central vagal stimulation, although bradycardia has also been observed after administration of quarternary amines. Pirezepine, a selective M1-antagonist, causes bradycardia in therapeutic doses for which a peripheral mechanism is postulated. This hypothesis has been investigated in healthy volunteers.Atropine 0.5 mg caused significant bradycardia from 210 min and pirenzepine 10 mg after 60 min. After prior beta-blockade, the bradycardic action of the anti-cholinergic drugs was more marked. Pirenzepine-induced bradycardia was reversed by higher doses of atropine.It is suggested that atropine- and pirenzepine-induced bradycardia results from M1-blockade of sympathetic ganglia. In addition, low concentrations of atropine and therapeutic doses of pirenzepine may cause an increase in acetylcholine, perhaps due to a presynaptic effect on nerve endings.

Dexfenfluramine-induced prolactin release as an index of central synaptosomal 5-hydroxytryptamine during treatment with fluoxetine

Serotonin (5-HT) stimulates prolactin release. In the present study the ability of dexfenfluramine to increase serum prolactin was used as an index of central 5-HT function after acute and chronic pretreatment of volunteers with fluoxetine.Following a single-blind, random design, on each experimental day each volunteer received 60 mg dexfenfluramine taken with 250 ml water at zero time and no other treatment, or pretreatment with 40 mg fluoxetine at -8 h, or pretreatment with 20 mg fluoxetine daily for 14 days, or the dexfenfluramine alone 14 days after cessation of 14 days of fluoxetine treatment.There were no significant differences between the prolactin levels found after dexfenfluramine only, dexfenfluramine after a single dose of fluoxetine, and dexfenfluramine 14 days after cessation of fluoxetine treatment. However, baseline levels and those 3 and 4 h after dexfenfluramine administration were significantly lower after pretreatment for 14 days with fluoxetine compared to the other three regimens. At 5 h the levels were still lower, but not significantly so, as the prolactin level rose approximately 110% compared to the baseline and 4 h values.The reduction in the median basal serum prolactin level by almost two-thirds after 14 days of fluoxetine treatment suggests a decrease in 5-HT turnover. Furthermore, the delayed surge in prolactin release produced by dexfenfluramine with this regimen suggests 5-HT release from a less accessible pool or accumulation of fluoxetine in the neuronal cytosol and consequent competitive inhibition of 5-HT transport out of the nerve terminal.5-HT turnover is reduced in depression. The present results suggest similar impairment of central 5-HT function in normal volunteers treated with fluoxetine. Thus, rather than cause an increase in 5-HT turnover, anti-depressants may correct defects in the 5-HT system. We speculate that anti-depressant treatment which decrease 5-HT turnover may lead to disturbed aggression regulation and violent self-destructive impulses.

Fraction of theophylline in sustained-release formulation which is absorbed from the large bowel

SummaryIn a cross-over study of six healthy male volunteers, 500 mg theophylline was administered either as plain tablets or in a sustained release preparation. On each occasion 2 g of non-enteric coated sulphasalazine was administered simultaneously as the time of appearance of sulphapyridine, the product of hydrolysis, in the blood provides an approximation of the oral — caecal transit time. The mean fraction absorbed — time profile was calculated from serial serum concentration measurements of theophylline by a modification of the Wagner-Nelson equation. The mean cumulative fraction of the dose absorbed following administration of the plain tablets was maximal at 3 h i.e. approximately 3 h ahead of the mean oral-caecal transit time, which was 5.9 h. Thus complete absorption occurred in the small intestine.With the sustained — release formulation, approximately only half of the dose was absorbed at the time the medication reached the large bowel i.e. at about 5.4 h. Absorption continued and at least 38% of the administered dose was additionally absorbed over the next 25 h.A reliable lengthened dosage interval is therefore possible with this particular sustained — release formulation.

Effects of glycopyrrolate on capsaicin-induced cough in normal volunteers treated with captopril

The effects of inhibition of angiotensin converting enzyme (ACE) and glycopyrrolate on cough caused by inhaled capsaicin were investigated in a double-blind, randomised cross-over study in twelve normal volunteers. The capsaicin challenge was performed before and 2 h after dosing with 75 mg captopril or matched placebo given orally, and 20, 40 and 60 min after giving 1 mg glycopyrrolate IV to each subject.Captopril and placebo did not alter the cough response when compared to baseline. Glycopyrrolate, however, caused a significant increase in the threshold sensitivity (D2) from baseline, and a significant decrease in the total cough response at 40 and 60 min both after captopril and placebo. The D2-baseline and D2-40 min after glycopyrrolate (mean (SD), respectively, were 3.2 (1.0); 17.9 (4.2) after placebo and 2.5 (8.5); 23.6 (6.9) after captopril.Elimination of vagal influences implies attenuation of the effects of tachykinins but not those prostaglandins. We postulate that tachykinins, such as substance P, play a more important role than prostaglandins in capsaicin-induced cough.We conclude that the vagus is important in the capsaicin-induced cough reflex, but, as suppression of this reflex by glycopyrrolate was delayed, the relevant receptors are either poorly accessible peripheral receptors or they are located in the central nervous system.

Effect of longterm cetirizine treatment on the cutaneous hypersensitivity reaction in patients with grass pollen allergy

In short-term studies cetirizine effectively reduces the early and late phases of the cutaneous hypersensitivity reaction. The aim of this study was to determine its long-term effects on both the vascular and cellular components of the reaction.The skin blister technique was used to collect inflammatory cells after intradermal administration of grass pollen antigen to 10 atopic volunteers. They were treated for 3 months with 10 mg cetirizine twice daily. Tests were done at baseline, before, and 7, 30 and 90 days after initiation of treatment. Blister fluid containing cells was collected on microscope slides at 6 and 24 hours. The area of induration was measured at 0.25, 1, 6, 10 and 24 h.Cetirizine significantly reduced the peripheral blood eosinophil count at 30 and 90 days (75% and 40% reduction respectively); there was no significant change after only one weeks therapy. Eosinophil recruitment to and activation in the area of antigen administration were already maximally reduced after 7 days, namely a reduction of 54, 52 and 59% at 10 h, and of 55, 68 and 66% at 24 h, respectively, at 7, 30 and 90 days. The area of induration was significantly reduced after one week of therapy. There was a general tendency towards an increase in the reduction at 30 and 90 days, which reached significance only at the 24 h observation; there was a 24, 51 and 48% reduction from baseline at, respectively, 7, 30 and 90 days.The data clearly show a progressive reduction of induration as well as of cellular events over time. The maximum effect occurred at 30 days, after which no further reduction was detected up to 90 days.We conclude that this progressive suppression of inflammation is possibly due to the inhibitory effect of cetirizine on the release of cytokines and other mediators of the hypersensitivity reaction.

Aldosterone response to metoclopramide is mediated through the autonomic nervous system in man

SummaryThis study primarily examines the role of the autonomic nervous system in the aldosterone response to metoclopramide since there is conflicting evidence as to the involvement of a dopaminergic mechanism in this response.Six normal male volunteers in metabolic balance at 100 mmol sodium/day and 60 mmol potassium/day constant intake received metoclopramide, 10 mg i.v., on five different occasions. The dosing was either metoclopramide alone or combined with ganglionic, muscarinic, β-adrenergic or calcium-channel blockade.Metoclopramide increased serum aldosterone significantly to 163.3% of basal level at 10 min. Atropine blunted this response and the 10 min level was significantly reduced to 116.03% of the basal value. The highest aldosterone levels were attained when metoclopramide was administered during a trimethaphan infusion and a peak of 292.8% of basal level occurred at 90 min. In the presence of atenolol, with or without nifedipine, the metoclopramide-induced aldosterone response was significantly greater at 15 min than with metoclopramide alone.The results of this investigation suggest that the aldosterone response to metoclopramide is mediated by acetylcholine released from post-ganglionic cholinergic nerve terminals, and that an adrenergic mechanism exerts a tonic inhibitory influence on aldosterone secretion in man.

Drug interactions with urate excretion in man

SummaryThe effects of pyrazinamide and ampicillin on the uricosuric response to probenecid and benzbromarone were studied in six normal subjects. The amount of uric acid was calculated for the 24 h volume of urine and the urate and creatinine clearances were determined for each of three urinary collection periods in order to calculate the percentage Curate/Ccreatinine.Ampicillin alone caused a significant uricosuria in the 0–2 h (p<0.025) and 8–24 h (p<0.025) periods. Benzbromarone caused a significant reduction in all the parameters.These observations suggest that high concentrations ampicillin compete with uric acid for reabsorption, but that its delayed uricosuric action can be ascribed to the binding of this dipeptide to a charge-mediated receptor site on the brush border membrane of proximal tubular cells. It would also appear that benzbromarone is secreted by the pyrazinamide-sensitive mechanism for urate secretion as it can cause a paradoxical retention of urate, but leaves the other probenecid-sensitive secretory transport process unoccupied as indicated by the fact that it does not change the kinetics of ampicillin.