Evaluation of hypothalamic-pituitary-adrenal axis in amenorrhoeic women with insulin-dependent diabetes.
Diabetes is associated with a higher incidence of secondary hypogonadotrophic amenorrhoea. In amenorrhoeic women with insulin-dependent diabetes a derangement in hypothalamic-pituitary-ovary axis has been proposed. No data exist on hypothalamic-pituitary-adrenal function in these women. Gonadotrophin releasing hormone (GnRH), corticotrophin releasing hormone (CRH), metoclopramide and thyroid releasing hormone (TRH) tests were performed in 15 diabetic women, eight amenorrhoeic (AD) and seven eumenorrhoeic (ED). Frequent blood samples were taken during 24 h to evaluate cortisol plasma concentrations. There were no differences between the groups in body mass index, duration of diabetes, insulin dose and metabolic control. The AD women had lower plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, oestradiol, androstenedione and 17-hydroxyprogesterone (17-OHP) than the ED women. The responses of pituitary gonadotrophins to GnRH, and of thyroid stimulating hormone (TSH) to TRH, were similar in both groups. The AD women had a lower prolactin response to TRH and metoclopramide, and lower ACTH and cortisol responses to CRH, than the ED women. Mean cortisol concentrations > 24 h were higher in the amenorrhoeic group. Significant differences in cortisol concentrations from 2400 to 1000 h were found between the two groups. Insulin-dependent diabetes may involve mild chronic hypercortisolism which may affect metabolic control. Stress-induced activation of the hypothalamic-pituitary-adrenal axis would increase hypothalamic secretion of CRH. This would lead directly and perhaps also indirectly by increasing dopaminergic tonus to inhibition of GnRH secretion and hence hypogonadotrophic amenorrhoea. Amenorrhoea associated with metabolically controlled insulin-dependent diabetes is a form of functional hypothalamic amenorrhoea that requires pharmacological and psychological management. (+info)
Bromocriptine in Parkinsonism: long-term treatment, dose response, and comparison with levodopa.
Thirty-seven patients with Parkinsonism were treated with bromocriptine 2.5-300 mg daily. Bromocriptine, alone or combined with levodopa, caused a 20-30% reduction in disability scores in 11 patients treated for one year. Tolerance did not develop during this period. Bromocriptine treatment was not of value in six patients who had previously not responded or who had lost their response to levodopa. However, in four of five patients with response swings on levodopa due to rapid changes in plasma dopa levels, the addition of bromocriptine caused a more stable response. Dose response curves to bromocriptine 12.5, 25, 50, and 100 mg and to levodopa 250, 500, 1000, and 2000 mg were studied in seven patients. Levodopa 2 g had a greater therapeutic effect and caused a greater rise in plasma growth hormone concentration than bromocriptine 100 mg. Levodopa caused emesis more commonly and hallucinations less commonly than bromocriptine. Bromocriptine appears to be a less potent stimulant than dopamine, and has both pre- and post-synaptic effects. Metoclopramide 60 mg oral was given 30 minutes before bromocriptine or levodopa to establish whether this caused dopamine-receptor blockade. Metoclopramide acted as a competitive antagonist to the anti-Parkinsonism and growth hormone effect of both drugs and in individual cases prevented emesis and hallucinations. The fall in blood pressure due to bromocriptine or levodopa was not antagonised by metoclopramide. Central and peripheral vascular dopamine receptors may be different in nature. (+info)
Influence of metoclopramide on plasma cholinesterase and duration of action of mivacurium.
Mivacurium is metabolized by plasma cholinesterase (PCHE). Metoclopramide inhibits PCHE in vitro and in vivo. We have assessed the effect of metoclopramide on duration of action of mivacurium and measured PCHE at baseline and at the time of maximal block. In a randomized, double-blind study, 30 patients received metoclopramide 0.15 mg kg-1 i.v. or saline, followed by propofol anaesthesia and mivacurium 0.15 mg kg-1. Using a TOF-Guard accelerometer, times to recovery of TI to 25%, 75% and 90% were 13.4, 19.3 and 21.9 min in the saline group and 17.8, 25.3 and 28.8 min in the metoclopramide group (P < 0.01, P < 0.05, P < 0.05, respectively). There were no differences in onset time or recovery index between the groups. PCHE activity at the time of maximum block decreased within each group (P < 0.01) but there was no difference between groups. In a second biochemical study of eight patients, a small decrease in PCHE activity was detected after metoclopramide 0.15 mg kg-1, but before administration of mivacurium (P < 0.025). We conclude that metoclopramide prolongs the duration of action of mivacurium. (+info)
Conditioning to injection procedures and repeated testing increase SCH 23390-induced catalepsy in mice.
The cataleptic behavior induced by the dopamine D1 antagonist SCH 23390 (SCH) has proven to be a useful assay for investigating the sensitivity of D1-like dopamine receptor-mediated effects during chronic drug administration. A fundamental flaw in most of these studies may be the involvement of the "repeated measures effect," a behavioral phenomenon well demonstrated for neuroleptic-induced catalepsy but not yet investigated for dopamine D1 antagonists. In this study, mice exposed for various sessions to the bar test presented a strong sensitization to the cataleptic behavior induced by repeated SCH treatment. Conversely, single tested animals exhibited a trend toward decreased catalepsy after repeated SCH treatment, which was in line with the development of a D1-like dopamine receptor supersensitivity suggested by an increase in SKF 38393-induced grooming behavior. Surprisingly, a challenge intraperitoneal saline injection increased the cataleptic behavior of single tested mice after long-term SCH treatment. This "injection-conditioned catalepsy" was also observed after repeated treatment with the dopamine D2 antagonists, haloperidol and metoclopramide. While these findings seem to explain some important contradictory data in the literature, they provide a new and simple animal model of the placebo effect. (+info)
Effect of different prokinetic agents and a novel enterokinetic agent on postoperative ileus in rats.
BACKGROUND/AIM: The effects of different prokinetic agents, the motilide erythromycin and the substituted benzamides metoclopramide and cisapride, were investigated in a rat model of postoperative ileus. These effects were compared with that of granisetron, a 5-hydroxytryptamine (5-HT(3)) receptor antagonist, and a novel enterokinetic agent, prucalopride, a 5-HT(4) receptor agonist. METHODS: Different degrees of inhibition of gastrointestinal transit, measured by the migration of Evans blue, were achieved by skin incision, laparotomy, or laparotomy plus mechanical stimulation of the gut. RESULTS: Metoclopramide decreased the transit after laparotomy with or without mechanical stimulation, whereas cisapride increased it after all three operations. Granisetron had no effect on the transit after the three operations when given alone. Prucalopride tended to increase the transit after laparotomy with or without mechanical stimulation when given alone. However, statistical significance was only reached when prucalopride was combined with granisetron. Erythromycin, a motilin receptor agonist, did not improve postoperative ileus in the rat. CONCLUSIONS: Cisapride, but not metoclopramide or erythromycin, is able to improve postoperative ileus in the rat. The results suggest that a combination of 5-HT(3) receptor antagonist and 5-HT(4) receptor agonist properties may be required to obtain a beneficial effect on surgery induced ileus in the rat. Furthermore, they indirectly indicate that stimulation of the excitatory mechanisms is not able to overcome the inhibitory influence of the neural reflex pathways activated during abdominal surgery. (+info)
Renal distal tubular handling of sodium in central fluid volume homoeostasis in preascitic cirrhosis.
BACKGROUND/AIMS: Patients with preascitic liver cirrhosis have an increased central plasma volume, and, for any given plasma aldosterone concentration, they excrete less sodium than healthy controls. A detailed study of the distribution of sodium reabsorption along the segments of the renal tubule, especially the distal one, is still lacking in preascitic cirrhosis. METHODS: Twelve patients with Child-Pugh class A cirrhosis and nine control subjects (both groups on a normosodic diet) were submitted to the following investigations: (a) plasma levels of active renin and aldosterone; (b) four hour renal clearance of lithium (an index of fluid delivery to the loop of Henle), creatinine, sodium, and potassium; (c) dopaminergic activity, as measured by incremental aldosterone response to intravenous metoclopramide. RESULTS: Metoclopramide induced higher incremental aldosterone responses, indicating increased dopaminergic activity in patients than controls, which is evidence of an increased central plasma volume (+30 min: 160.2 (68.8) v 83.6 (35.2) pg/ml, p<0.01; +60 min: 140.5 (80.3) v 36. 8 (36.1) pg/ml, p<0.01). Patients had increased distal fractional sodium reabsorption compared with controls (26.9 (6.7)% v 12.5 (3. 4)% of the filtered sodium load, p<0.05). In the patient group there was an inverse correlation between: (a) absolute distal sodium reabsorption and active renin (r -0.59, p<0.05); (b) fractional distal sodium reabsorption and sodium excretion (r -0.66, p<0.03). CONCLUSIONS: These data suggest that in preascitic cirrhosis the distal fractional tubular reabsorption of sodium is increased and critical in regulating both central fluid volume and sodium excretion. (+info)
Metoclopramide: a novel adjunct for improving cardiac and hepatocellular functions after trauma-hemorrhage.
Although metoclopramide (MCP) administration after trauma-hemorrhage restores the depressed immune functions, it remains unknown whether this agent has any salutary effects on the depressed cardiovascular and hepatocellular functions under those conditions. Adult male Sprague-Dawley rats underwent a midline laparotomy (i.e., induction of soft-tissue trauma) and were then bled to and maintained at a mean arterial pressure (MAP) of 40 mmHg until 40% of the maximal shed blood volume was returned in the form of Ringer lactate (RL). The rats were then resuscitated with four times the shed blood volume in the form of RL over 60 min. MCP (2 mg/kg body wt) or vehicle was administered subcutaneously at the end of resuscitation. At 24 h after resuscitation, cardiac index and hepatocellular function (i.e., the maximum velocity and the overall efficiency of indocyanine green clearance) were determined. Plasma levels of interleukin (IL)-6 and prolactin were also assayed. The results indicate that treatment with MCP after trauma-hemorrhage and resuscitation significantly improved the depressed cardiac output and hepatocellular function. Furthermore, MCP administration significantly increased circulating levels of prolactin and decreased the plasma levels of the proinflammatory cytokine IL-6. Thus, administration of MCP, which increased prolactin secretion, appears to be a useful adjunct for restoring the depressed cardiac and hepatocellular functions and downregulating inflammatory cytokine release after trauma and hemorrhagic shock. (+info)
Metoclopramide in the prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized, placebo-controlled studies.
Metoclopramide has been used for almost 40 yr to prevent postoperative nausea and vomiting (PONV). We have reviewed the efficacy and safety of metoclopramide for the prevention of PONV. A systematic search (MEDLINE, EMBASE, manufacturers' databases, hand searching, bibliographies, all languages, up to June 1998) was performed for full reports of randomized comparisons of metoclopramide with placebo in surgical patients. Relevant end-points were prevention of early PONV (within 6 h after operation), late PONV (48 h) and adverse effects. Combined data were analysed using relative benefit/risk and number-needed-to-treat/harm. In 66 studies, 3260 patients received 18 different regimens of metoclopramide, and 3006 controls received placebo or no treatment. There was no evidence of dose-responsiveness with oral, i.m., intranasal or i.v. metoclopramide in children and adults. In adults, the best documented regimen was 10 mg i.v. There was no significant anti-nausea effect. The numbers-needed-to-treat to prevent early and late vomiting were 9.1 (95% confidence intervals 5.5-27) and 10 (6-41), respectively. In children, the best documented regimen was 0.25 mg kg-1 i.v. The number-needed-to-treat to prevent early vomiting was 5.8 (3.9-11). There was no significant late anti-vomiting effect. Minor drug-related adverse effects (sedation, dizziness, drowsiness) were not significantly associated with metoclopramide. There was one adult who experienced extrapyramidal symptoms with metoclopramide. (+info)