Metoclopramide,domperidone and dopamine in man: actions and interactions

Summary The effects of oral doses of the dopamine antagonist antiemetics metoclopramide and domperidone on baseline and dopamine stimulated renal function and systemic haemodynamics were assessed in a placebo controlled crossover study in 9 healthy volunteers.Metoclopramide did not change baseline ERPF, GFR or FF over 2 h post dosing but it significantly reduced baseline U_NaV, U_KV, urine flow, urinary dopamine excretion, supine and erect diastolic blood pressure and supine systolic blood pressure. Domperidone and placebo did not cause these effects.Metoclopramide caused a marked rise and domperidone a small fall in plasma aldosterone concentration (PAC) but placebo was without effect. Neither antiemetic altered plasma renin activity (PRA) but a small fall occurred with placebo.Two hours after pretreatment with placebo dopamine (2 g/kg/min) increased effective renal plasma flow (ERPF), glomerular filtration rate (GFR), sodium excretion rate (U_NaV), urine flow rate, urinary dopamine excretion rate, supine systolic blood pressure and supine and erect pulse rate and decreased the potassium excretion rate (U_KV), filtration fraction (FF) and supine diastolic blood pressure.Metoclopramide pretreatment, did not attenuate the dopamine induced rise in ERPF, GFR, urine flow, urinary dopamine excretion or supine systolic blood pressure but it did attenuate the rise in pulse rate, the fall in diastolic pressure, and the antikaliuretic effect of dopamine leading to a net kaliuresis when compared to placebo. Domperidone was similar to placebo.Neither metoclopramide nor domperidone given orally caused clinically important antagonism of the renal haemodynamic effects of dopamine. However the effects of metoclopramide on blood pressure and electrolyte excretion may have clinical importance.Metoclopramide has significant pharmacodynamic effects which are probably not due to DA₂ antagonism but may be mediated by DA₁ antagonism or be non-specific.Abbreviations DA dopamine - ERPF effective renal plasma flow - FF filtration fraction - GFR glomerular filtration rate - PAC plasma aldosterone concentration - PRA plasma renin activity - UV urine flow rate - U_NaV urinary sodium excretion rate (natriuresis) - U_KV urinary potassium excretion rate (kaliuresis) - HPLC high performance liquid chromatography.     

A comparison of the myocardial metabolic and haemodynamic changes produced by propofol-sufentanil and enflurane-sufentanil anaesthesia for patients having coronary artery bypass graft surgery

The purpose of this study was to compare propofol-sufentanil with enflurane-sufentanil anaesthesia for patients undergoing elective coronary artery bypass graft (CABG) surgery with respect to changes in (1) haemodynamic variables; (2) myocardial blood flow and metabolism; (3) serum cortisol, triglyceride, lipoprotein concentrations and liver function; and (4) recovery characteristics. Forty-seven patients with preserved ventricular function (ejection fraction greater than 40%, left ventricular end diastolic pressure less than or equal to 16 mmHg) were studied. Patients in Group A (n = 24) received sufentanil 0.2 microgram.kg-1 and propofol 1-2 mg.kg-1 for induction of anaesthesia which was maintained with a variable rate propofol (50-200 micrograms.kg-1.min-1) infusion and supplemental sufentanil (maximum total 5 micrograms.kg-1). Patients in Group B (n = 23) received sufentanil 5 micrograms.kg-1 for induction of anaesthesia which was maintained with enflurane and supplemental sufentanil (maximum total 7 micrograms.kg-1). Haemodynamic and myocardial metabolic profiles were determined at the awake-sedated, post-induction, post-intubation, first skin incision, post-sternotomy, and pre-cardiopulmonary bypass intervals. Induction of anaesthesia produced a larger reduction in systolic blood pressure in Group A (156 +/- 22 to 104 +/- 20 mmHg vs 152 +/- 26 to 124 +/- 24 mmHg; P less than 0.05). No statistical differences were detected at any other time or in any other variable including myocardial lactate production (n = 13 events in each group), time to tracheal extubation and time to discharge from the ICU. We concluded that, apart from hypotension on induction of anaesthesia, propofol-sufentanil anaesthesia produced anaesthetic conditions equivalent to enflurane-sufentanil anaesthesia for CABG surgery.     

Tumorigenicity of 7, 12-dimethylbenz[a]anthracene, its hydroxy-methylated derivatives and selected dihydrodiols in the newborn mouse

The newborn mouse lung adenoma model has been shown to be asensitive test for studying the tumor-igenicity of bay regiondiol epoxides and their precursor dihydrodiols. When a totaldose of 28 nmol of 7, 12-dimethylbenz[a]anthracene (DMBA) orits derivatives was injected i.p. into the preweaning mice,it was found that the 3, 4-dihydrodiols of both DMBA and 7-hy-droxymethyl-12-methylbenz[a]anthracenecaused 13.3 and 4.1 times more lung adenomas than DMBA, respectively.The mice treated with the 5, 6- and 8, 9-dihydro-diols of DMBA,7-hydroxymethyl-12-methylbenz[a]-anthracene and its 5, 6- 8,9-and 10,11-dihydrodiols, 7-methyl-12-hydroxymethylbenz[a]an-thraceneand 7,12-dihydroxymethylbenz[a]anthracene developed a levelof lung adenomas/mouse less than Mold higher than that foundin the DMSO-treated control group. Liver tumors also developedin some of the mice. The percentage of mice with liver tumorsalso indicated that the 3, 4-dihydrodiols of both DMBA and 7-hydroxymethyl-12-methylbenz[a]anthracenewere more tumorigenic than DMBA itself. These data indicatethat the 3, 4-dihydrodiols of both DMBA and its 7-hydroxymethylderivative may be proximate carcinogenic metabolites of DMBAin the newborn mouse.     

An unusually severe phenotype for familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is a dominantly inherited predisposition to the development of many hundreds to thousands of adenomatous polyps of the colon. The mean age of onset is around 15 years, symptoms may arise in the third decade, and the median age for the development of colonic cancer is 35-40 years. Prophylactic colectomy reduces the risk of death from colorectal cancer to such an extent that late sequelae such as upper gastrointestinal tumours have become the main cause of mortality in appropriately managed patients. The age at which colonic surveillance begins reflects the natural history of the disease. Onset of polyp formation and cancer in childhood is very unusual, but has recently been associated with a specific mutation at codon 1309 in exon 15 where a more severe phenotype is sometimes observed. The case histories of two families are reported in which there is childhood onset of polyps in the youngest generation and in one case a carcinoma, in whom mutations have been identified in exon 11 of the APC gene. Several other affected relatives were diagnosed at ages ranging from 5-48 years, some already with a cancer at the time of first screening. Since the aim of screening for colonic polyps is prevention of colonic cancer, family members at risk should be offered genetic assessment and direct mutation testing where this is possible, usually in the early teens. In the absence of a genetic test (the situation in about one third of families) or in a known gene carrier, annual colonoscopy examination is advised from the same age. Clinicians should take note of the family history and be prepared to consider much earlier intervention if symptoms occur in a child with a family history of FAP. Where childhood onset of polyps has occurred, other children at risk in the family must be offered earlier genetic testing and endoscopic surveillance.

     

Does a single plasma phenylalanine predict quality of control in phenylketonuria?

A 1993 MRC working group on phenylketonuria suggested standardising blood phenylalanine measurements by taking blood samples at the same time each day. Since it is not known how representative of a 24 hour period a single phenylalanine concentration is, the aim of this study was to investigate the 24 hour variability of plasma phenylalanine in well controlled children with phenylketonuria. Sixteen subjects, 12 girls and four boys aged 1 to 18 years, had hourly venous blood samples collected for 13 hours between 09.00 and 21.00 on one day. Serial skin puncture blood specimens were then collected at 24.00, 03.00, and 06.00 within the same 24 hour period. All food and drink was weighed. The median variation in plasma phenylalanine concentration was 155 mumol/l/day, with a minimum of 80 and a maximum of 280. The highest concentration occurred in the morning between 6.00 and 9.00 in 63% of subjects; the lowest occurred between midday and midnight in 94%. Concentrations < 100 mumol/l occurred in 46% of children below 11 years, three having concentrations < 30 mumol/l for two, six, and seven hours respectively. Three of five subjects had concentrations above the MRC guidelines for 24% of the period studied. Except in two subjects, the blood concentrations did not rise in response to phenylalanine consumption. However, the greater the quantity of protein substitute taken between waking and the 16.00 specimen, the larger the decrease in daytime phenylalanine concentration (r = -0.7030) (p < 0.005). There is therefore wide variability in phenylalanine concentrations in a 24 hour period in children with phenylketonuria which is not reflected in a single observation. Further study is needed to investigate the effects of timing of protein substitute on the stability of phenylalanine concentrations.     

Randomised controlled trial of advice on an egg exclusion diet in young children with atopic eczema and sensitivity to eggs

Background: The role of exclusion diets in the management of atopic eczema in young children is uncertain. This randomised controlled trial evaluates the effect of excluding egg from the diet in young children with atopic eczema and sensitivity to eggs. Fifty-five such children were randomised either to a 4-week regimen, in which mothers were given general advice on care of eczema and additional specific advice from a dietician about an egg exclusion diet (diet group), or to a control group in which general advice only was given. Both groups continued conventional topical treatment. Disease activity was assessed by estimates of the surface area affected by eczema and by an arbitrary severity score. Possible egg sensitivity was identified by RAST before randomisation and after the trial by double-blind placebo-controlled egg challenge. Results: The mean reduction in surface area affected by eczema was significantly greater (p = 0.02) in the group receiving dietary advice (from 19.6% to 10.9% area affected) than in the control group (from 21.9% to 18.9%). A significant improvement also occurred in severity score (p=0.04): from 33.9 to 24.0 units for the diet group compared with a decrease from 36.7 to 33.5 in the control group. The study suggests that advice on the dietary exclusion of eggs is useful as part of the overall management of young children with atopic eczema and sensitivity to eggs.     

Acute changes in urine protein excretion may predict chronic ifosfamide nephrotoxicity: a preliminary observation

Purpose: To evaluate proteinuria occurring early after ifosfamide therapy and to assess the use of changes in proteinuria in the prediction of severe chronic nephrotoxicity. Methods: One-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis was used to characterize urine protein excretion in 12 children with solid tumours before and after the first course of ifosfamide treatment, and in 24 healthy children. Chronic nephrotoxicity was evaluated at 6 months after ifosfamide treatment and graded as none, mild, moderate or severe. Results: Urine from healthy children and from 10 of 12 patients before ifosfamide therapy showed a protein band with a molecular weight (95.4 kDa) corresponding to that of Tamm-Horsfall protein but no lower molecular weight proteins. After the first course of ifosfamide this 95.4-kDa protein was lost in six of ten patients with a concomitant appearance of a low molecular weight proteinuria (<70 kDa) in eight. Tamm-Horsfall protein was lost in two of five patients who subsequently developed no or mild nephrotoxicity and in four of five patients who subsequently developed moderate or severe nephrotoxicity. Conclusions: Early subclinical changes in urine protein excretion after ifosfamide, manifested by a loss of Tamm-Horsfall protein excretion, may be predictive of subsequent chronic nephrotoxicity. Received: 27 August 1996 / Accepted: 25 July 1997     

AMPA receptor subunit expression in trigeminal neurons during postnatal development

Trigeminal motoneurons (Mo5) and mesencephalic trigeminal neurons (Me5) are important constituents of the neural circuitry responsible for jaw movements. Non-N-methyl-D-aspartate (NMDA) glutamate receptors are a critical component of the brainstem circuitry responsible for reflex and centrally activated jaw movements; however, little is known about the expression of these receptors in neonatal oral-motor circuitry. Receptor immunohistochemistry using affinity-purified polyclonal antibodies directed against GluR1, GluR2/3/4c, and GluR4, respectively, and a monoclonal antibody directed against the GluR2 subunit, were used in rats at postnatal day (P)1, P3, P5, P10, P19-21, P32-35, and P60 to describe the expression of the alpha-amino-d-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor in Mo5 and Me5 neurons. In Mo5, immunoreactivity was noted for all antibodies throughout the time frame sampled. Neurons in caudal portions of Me5 displayed immunoreactivity to each antibody except at P60 when GluR2 immunoreactivity was absent. Neurons located in rostral Me5 displayed GluR2/3/4c and GluR4 immunoreactivity throughout the time frame, GluR1 immunoreactivity emerged at P3 and a transient expression of GluR2 expression was observed between P10 and P32-35. The lack of labeling of some neurons in both regions, coupled with differences in temporal expression, suggests that there are differences in the AMPA receptor phenotype within and between Mo5 and Me5 during postnatal development. Differences in AMPA subunit composition suggest a complex role for AMPA-mediated glutamatergic neurotransmission in brainstem circuits controlling jaw movements.