Genetic polymorphism of CYP2D6 and CYP2C19 in east- and southern African populations including psychiatric patients.

OBJECTIVES: The study was carried out to investigate the distribution of cytochrome P450 2D6 (CYP2D6) and CYP2C19 genotype frequencies in three African populations and to compare these frequencies between healthy individuals and psychiatric patients. METHODS: Three hundred and eighty-four subjects from South Africa (Venda), Tanzania, and Zimbabwe who consented to the study were genotyped for CYP2D6 (CYP2D6*1, *2, *3, *4, *5, and *17) and CYP2C19 (CYP2C19*1, *2, and *3) by PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism) techniques. RESULTS: The genotypes for CYP2D6 predicted a poor metabolizer frequency of 2.3% (2/88) in Tanzanian psychiatric patients, 1.9% (2/106) in Tanzanian healthy controls and 2.6% (2/76) in the South African Venda. The low-activity CYP2D6*17 allele frequency was higher in psychiatric patients (30%, 53/176) than in healthy individuals (20%, 43/212) in Tanzanians. The frequencies for CYP2C19*2 genotypes were predictive of a low prevalence of poor metabolizers (PMs). The CYP2C19*3 allele was absent in the three populations studied. There was no difference in CYP2D6 or CYP2C19 PM genotype frequencies between psychiatric patients and healthy subjects. CONCLUSION: The genotype results predict a low prevalence of people with deficient CYP2D6 and CYP2C19 activity among linguistically (Bantu) related populations of East and Southern Africa. The high frequency of the low-activity CYP2D6*17 allele predicts that the Bantu people have a reduced capacity to metabolise drugs that are CYP2D6 substrates.

Once versus twice daily amikacin in neonates: prospective study on toxicity.

OBJECTIVE: To compare the potentially toxic effects in fullterm neonates of amikacin administered once daily, versus amikacin administered twice daily. METHODOLOGY: A controlled, randomized, prospective study in which one group of fullterm neonatal patients received amikacin 15 mg/kg per dose once daily (n = 20), and the other received amikacin 7.5 mg/kg per dose twice daily (n = 20). Impairment of renal glomerular function was defined as a decline of less than 50% of the expected physiological drop in serum creatinine over time. Brainstem auditory evoked potentials were also evaluated and amikacin blood levels taken. RESULTS: Fifteen patients in the once-daily group and 12 patients in the twice-daily group demonstrated at least one period of renal function impairment while in hospital. This decreased to five of 16 and four of 16 patients during follow-up. These differences were not statistically significant. Brainstem auditory evoked potentials did not find signs of ototoxicity at any time. CONCLUSION: In fullterm neonatal patients, once daily dosing of amikacin is no more toxic than the twice daily regimen.

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.

Lack of bioavailability of mebeverine even after pretreatment with pyridostigmine.

OBJECTIVE: After the oral administration of mebeverine to animal or human, measurable concentrations of the drug have never been found in the plasma. The ex vivo hydrolysis of mebeverine can be blocked by esterase inhibitors. In the present study, human volunteers were pretreated with pyridostigmine to attempt to improve the bioavailability of the parent drug. METHODS: Following a single-blind, random design, 12 normal human volunteers received orally either placebo or 60 mg pyridostigmine, followed 2 h later by 405 mg mebeverine. Blood samples were drawn intermittently for 4 h and were spiked immediately with neostigmine in order to block ex vivo hydrolysis. RESULTS: Even after pretreatment with pyridostigmine, the plasma samples failed to reveal detectable concentrations of mebeverine. Pyridostigmine pretreatment mediated a significantly higher peak concentration of veratric acid, the acid moiety resulting from hydrolysis of mebeverine. CONCLUSION: As mebeverine seemingly undergoes complete presystemic hydrolysis, it seems unlikely that the effects of the drug could be mediated centrally. Furthermore, as it is unlikely that sufficient mebeverine traverses the intestine to exert a local effect on the colon (i.e., the time-course of veratric acid plasma levels does not support such a conclusion), the therapeutic effect of the drug, if any, has to be ascribed to an active metabolite. However, the hydrolysis products of mebeverine are not known to be pharmacologically active.

Effects of metoclopramide and tropisetron on aldosterone secretion possibly due to agonism and antagonism at the 5-HT4 receptor.

OBJECTIVE: Part of the prokinetic activity of metoclopramide can possibly be ascribed to agonist activity at 5-HT4 receptors. The 5-HT3 antagonist tropisetron is thought to act as an antagonist at 5-HT4 receptors. In the present study aldosterone secretion in response to the administration of these two drugs was explored to examine the role of the 5-HT4 receptor in aldosterone secretion. METHODS: Following a single-blind, random design, ten normal male volunteers received one of the following regimens on three occasions, with at least 2-week intervals: metoclopramide 10 mg i.v.; tropisetron 5 mg by slow i.v.i., or; tropisetron by slow i.v.i., followed by 10 mg metoclopramide i.v. RESULTS: In response to metoclopramide alone the mean plasma aldosterone level rose significantly to 149% of basal level and remained significantly elevated for the next 20 min. With tropisetron alone, there was a significant 37.8% drop at 60 min and the aldosterone levels remained low for the duration of the experiment. Metoclopramide reversed the decline mediated by tropisetron significantly at 30 and 90 min. Aldosterone levels after the latter regimen also did not differ significantly from baseline at any time period. CONCLUSION: These results would suggest the existence of a tonic stimulatory influence of 5-HT via 5-HT4 receptors on aldosterone secretion, which could be augmented by metoclopramide and blocked by tropisetron. However, the effect of tropisetron per se should be interpreted with caution given the lack of a saline group.

The proportional cumulative area under the curve of paracetamol used as an index of gastric emptying in diabetic patients with symptoms of gastroparesis.

1. The foreshortened 2 h method of measuring liquid gastric emptying (i.e. the proportional cumulative area under the curve of paracetamol) was utilized in diabetic patients in order to detect both gastroparesis and the influence of metoclopramide, a known prokinetic drug, on this condition. 2. Metoclopramide, 10 mg intravenously, caused a significant increase in the median PCAUC from 20 min onwards. 3. In this study delayed gastric emptying was defined as a %PCAUC without pretreatment lower than the 5% percentile at 40, 60 and 90 min for normal volunteers. According to this criterion seven of the 10 patients with clinical symptoms of gastroparesis and/or peripheral neuropathy had delayed gastric emptying. 4. The PCAUC method would therefore seem to be a reliable model for investigating gastric emptying in diabetics and the effects of various prokinetic drugs on this condition.

A noninvasive evaluation of baroreceptor sensitivity with the Valsalva maneuver and phenylephrine methods.

In a double-blind crossover study, we compared baroreceptor sensitivity (BS) and latency, derived from the phenylephrine method with BS and latency derived from phase IV of the Valsalva maneuver (VM), using the Finapres, a noninvasive blood pressure monitor. Ten healthy volunteers were enrolled in the study and BS was determined with placebo, atropine (0.03 mg/kg) and atenolol (10 mg) and was expressed as the linear relation between the change in RR interval following the blood pressure rise induced by either phenylephrine or phase IV of the VM (i.e., after cessation of straining). Baseline baroreceptor sensitivity (p<0.001) and baroreceptor sensitivity in the presence of atropine (p<0.02) was smaller with the VM but no differences in baroreceptor sensitivity between the two methods were evident after atenolol. Although no linearity existed between the two methods under any of the experimental conditions, baroreceptor sensitivity in the presence of atropine was significantly smaller (p<0.01)(and latency delayed (p<0.08)) compared to atenolol-induced changes with both methods. We found excellent correlation between baroreceptor sensitivity derived from the ECG tracing and Finapres recorded beat-to-beat pulse intervals (p<0.001; r>0.8, under all conditions) although the correlation after atropine was not as close (p<0.01; r=0.7). The smaller baroreceptor sensitivity induced by the Valsalva maneuver with placebo and atropine, but not with atenolol, suggests a parasympathetically influenced vasodilation, and sympathetically medicated tachycardia during phase IV of the VM.

The influence of betahistine on the dynamics of the cutaneous hypersensitivity reaction in patients with grass pollen allergy.

Histamine has been well documented as an immune modulator, but the dynamics of a number of histamine receptor agonists and antagonists have not been similarly established. The aim of this study was to determine the effect of betahistine (an H3-receptor blocker with partial H1- and H2-agonism) on the dynamics of the cutaneous hypersensitivity reaction. The skin blister technique was used to collect inflammatory cells after intradermal (i.d.) administration of grass pollen antigen, histamine and betahistine to 11 atopic volunteers. In this open, cross-over study, volunteers were randomly allocated to five treatment protocols i.e. (a) histamine 1 microgram i.d.; (b) betahistine 57, 114 and 285 micrograms i.d.; (c) i.d. grass pollen antigen; (d) (c) plus oral betahistine; (e) (c) plus oral betahistine, cetirizine, (H1-blocker) and cimetidine (H2-blocker). Blister fluid containing cells were collected on microscope slides at 6 and 24 h after i.d. injections. The areas of the wheal and flare and of induration were measured, respectively, at 0.25, and, 1, 6 and 24 h. Combined oral therapy with cetirizine, cimetidine and betahistine reduced the area of grass pollen-induced induration significantly at all time periods, but caused a significant increase in eosinophil and neutrophil vacuolisation during the late phase reaction. This did not occur with orally administered betahistine alone. Intradermal betahistine induced significantly more neutrophil and eosinophil vacuolization than histamine and, in contrast to the latter, also mediated a concentration-dependent late phase induration. The results of this study suggest that the H3-receptor regulates a feedback system in conjunction with that previously proven for the H2-receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of captopril and naloxone on the Valsalva manoeuvre and systolic time intervals in healthy volunteers.

1. The aim of the study was to ascertain whether the inhibition of the sympathetic nervous system by angiotensin-converting enzyme (ACE) inhibitors is mediated by endogenous opioids. Naloxone was used to evaluate the effects of the latter on systolic time intervals (STI) and Valsalva manoeuvre-induced blood pressure and heart rate changes. 2. Baseline recordings were done in 12 healthy male volunteers and repeated 2 h after oral administration of 75 mg of captopril and again after naloxone 0.4 mg/kg was administered intravenously over 10 min. 3. After captopril there was a significant reduction in systolic (P < 0.02) and mean blood pressure (P < 0.04) without any changes in heart rate. Furthermore, captopril increased the Valsalva ratio (P < 0.06) but did not influence inotropism as indicated by STI. Naloxone did not influence any of these findings. 4. The changes in the Valsalva ratio after captopril were mediated by an increase in the maximum bradycardia in nine of the 12 subjects. 5. The results indicate that endogenous opioids do not play a role in the putative sympatholytic effect of ACE inhibition.

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 i.v. 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.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

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 week's 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.(ABSTRACT TRUNCATED AT 250 WORDS)

The countering of diazoxide-induced vasodilatation by tenoxicam in normal volunteers.

The effect of the nonsteroidal anti-inflammatory drug, tenoxicam, on diazoxide-induced lowering of standing diastolic blood pressure was explored in 10 normal volunteers. With diazoxide there was a significant fall in the 5-min standing diastolic pressure, i.e. a median drop of 15.5, 11.0, 9.5 and 7.0 mm Hg at 10, 35, 75 and 105 min, respectively, but with the tenoxicam-diazoxide regimen this pressure did not differ significantly from baseline at any time point. Tenoxicam did not modify the diazoxide-induced changes in blood glucose and plasma insulin. It may be that prostaglandins normally contribute to the lowering of peripheral vascular resistance, or that acutely-administered diazoxide enhances the release of vasodilatory prostaglandins.

Placebo substitution for methyldopa in geriatric hypertensive patients.

The aim of this study was to obtain an objective evaluation of the possibly inappropriate antihypertensive therapy of elderly patients; this was done by means of placebo substitution for methyldopa, one of the drugs taken by all the participating patients. Forty patients were recruited from a hospital outpatient clinic and randomly allocated to two groups. One group remained on treatment which included methyldopa, while a matching placebo tablet was substituted in the other group. The study was conducted over a period of 6 months in a single-blind manner. Methyldopa was reintroduced in the placebo group when one of the evaluation clauses was recorded. Only 2 patients in the placebo group required reintroduction of methyldopa tablets. In the rest of this group there was no significant difference between systolic and diastolic pressures before and after 6 months of placebo substitution. Withdrawal of unnecessary antihypertensive therapy in the elderly should be considered. Patients must be observed carefully and therapy reintroduced when blood pressures rise.

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

In 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. Isradipine's apparent total body clearance and steady-state AUC remained unchanged. Ex vivo induced platelet aggregation was not affected by any of the treatments.

Effects of enhancement and antagonism of 5-hydroxytryptamine activity on the influence of metoclopramide on gastric emptying.

This study examines the influence of the serotonergic system on the effect of metoclopramide on gastric emptying. Six subjects received the following pretreatments before metoclopramide and paracetamol: fluoxetine (5-HT uptake inhibitor); meterogoline (5-HT1 antagonist); pizotifen (5-HT2 antagonist) or methysergide (5-HT1 and 5-HT2 antagonist). One regimen consisted of metoclopramide (5-HT3 antagonist and 5-HT4 agonist) alone. Gastric emptying was measured by the mean cumulative fraction absorbed-time profiles of paracetamol. Methysergide/metoclopramide significantly delayed gastric emptying from 30 min onwards. Metoclopramide with either metergoline or pizotifen did not retard gastric emptying to the same extent, suggesting a greater influence with simultaneous 5-HT1 and 5HT2 blockade. Metoclopramide/fluoxetine caused a significant decrease in the fractional absorption of paracetamol at 5 min when compared to the metoclopramide regimen. It was assumed that the influence of metoclopramide was not optimal at this stage, therefore possibly indicating domination of 5-HT3 over 5-HT4 effects, resulting in gastric delay. It therefore seems as if all the 5-HT receptors present in the gut have a role to play in the control of gastric emptying.