The discriminative stimulus effects of MK-801 in pigeons

The discriminative stimulus effects of MK-801 [(+)-5-methyl-10, 11-dihydroxy-5H-dibenzo (a,d) cyclohepten-5, 10-imine], a proposed noncompetitive N-methyl-D-aspartate (NMDA) antagonist, were studied in pigeons discriminating MK-801 from saline, responding being maintained by food. Compounds with noncompetitive NMDA antagonist effects in other preparations (PCP [0.18-5.6mg/kg], dextrorphan [1-32mg/kg], ketamine [1-32mg/kg] and dexoxadrol [1-10mg/kg]) produced MK-801-appropriate responding dose-dependently. The potency order for this effect, and for response rate decreasing effects, closely mirrored the potency order for these compounds in causing catalepsy, an effect believed to be mediated by antagonism at the NMDA receptor complex. NMDA (0.32-5.6mg/kg), morphine (1-10mg/kg) and pentobarbital (1-17.8mg/kg) produced almost no MK-801-appropriate responding. There were no consistent potency differences among the (+)-isomer (1-32mg/kg), the (-)-isomer (1-17.8mg/kg) and the racemate (1-17.8mg/kg) of SKF 10,047 in producing MK-801-appropriate responding. The competitive NMDA antagonist CGS 19755 (1-10mg/kg) produced partial MK-801-appropriate responding (maximum value = 77.8%) up to 8h after administration. The homogeneity of the discriminative stimulus effects among compounds with noncompetitive NMDA antagonist effects in vitro, as well as the partial substitution for MK-801 by CGS 19755, suggest that the MK-801 discriminative stimulus in pigeons is due to noncompetitive NMDA antagonism.     

Dose-response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine

The effects of oral administration of the ₂ adrenergic receptor antagonists idazoxan (20 mg, 40 mg, 80 mg) and yohimbine (20 mg) were compared using a placebo-controlled within-subjects design. Healthy subjects completed 5 test days during which medication effects on mood and anxiety states, physiologic indices, plasma cortisol levels, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were assessed. Idazoxan dose-dependently increased plasma MHPG, plasma cortisol, systolic and diastolic blood pressure, and Panic Attack Symptom Scale scores in healthy subjects. Overall, yohimbine and idazoxan produced a similar pattern of behavioral and neuroendocrine responses. Since idazoxan possesses relatively greater receptor specificity compared to yohimbine, it may be a more useful ₂ antagonist in humans.     

Dynamic SPECT imaging of dopamine D2 receptors in human subjects with iodine-123-IBZM.

We studied the uptake, distribution, metabolism and washout of the dopamine D2 receptor ligand [123I]IBZM in healthy subjects (n = 12) with dynamic brain SPECT. The highest radioactivity level was detected in the striatum. Operationally-defined striatal "specific" uptake peaked at 69 min postinjection of radioligand and showed a gradual decline of 15% per hour thereafter. "Specific" uptake at maximal counts represented 53% of the total striatal radioactivity. Two subjects received haloperidol (20 micrograms/kg i.v.) 80 min postinjection of radioligand. Haloperidol caused a 2.6-fold increase in the rate of washout of specific striatal activity in comparison to that in the 10 control subjects and was consistent with drug-induced displacement of radioligand from the dopamine D2 receptor. Two classes of metabolites were detected in plasma and urine: a polar fraction, not extracted by ethyl acetate, and a nonpolar, extractable fraction consisting of parent compound and two compounds having shorter retention times on reversed-phase HPLC. Greater than half the plasma parent was metabolized within 10-15 min after administration. The volume of distribution, estimated from the peak arterial plasma concentration at 50-75 sec, was 7.7-10.2 l; the free (nonprotein bound) fraction of [123I]IBZM after in vitro incubation with blood or plasma was 4.4% +/- 0.4%. These results suggest that [123I]IBZM exhibits uptake in brain regions with high D2 receptor density and shows a relatively stable washout during which drugs affecting dopaminergic transmission may be administered.     

Is the VBR still a useful measure of changes in the cerebral ventricles?

Standard methods of ventricular measurement with computed tomography (CT) and magnetic resonance imaging (MRI) allow for as much as a 10-mm variation in the level of the "best" axial slice through the lateral ventricles. In a series of 10 patients who received MRI scans, the effect of 1-mm variations in slice center level on measured ventricle-brain ratio (VBR) was determined; even variations as small as 1 mm can result in a 10% change in VBR. The amount of within-subject variability in VBR that could result from this factor alone appears to be more than twice as large as that encountered with direct volume measurements, indicating that the latter measure would be at least twice as sensitive to real changes in ventricular size as the VBR.     

Secondary hyperparathyroidism and osteopenia in women following gastric exclusion surgery for obesity

Gastric exclusion has been introduced as a surgical treatment for morbid obesity. We describe two women who had undergone gastric bypass for obesity with metabolic bone disease and secondaryhyperparathyroidism. In one patient transiliac bone biopsy after double tetracycline labelling demonstrated histologic evidence of hyperparathyroidism with osteitis fibrosa cystica. Six additional women who had undergone gastric exclusion were evaluated. Serum phosphorus, calcium, and creatinine were normal in all but one patient who had hypocalcemia. Serum immunoreactive parathyroid hormone was elevated in seven of eight patients and urinary calcium was 2 mmol/d (80 mg/24 h) in 6 patients. Lumbar spine bone mineral density was 86±7 (mean±SE) per cent of predicted and femoral neck bone mineral density was 89±6 per cent of predicted. Women who have had gastric exclusion for obesity may develop secondary hyperparathyroidism which could result in loss of bone mass.Deceased     

A modified prognostic index based upon nutritional measurements

This paper describes a formula which, on solution, derives a prognostic index (PI) for predicting surgical complications using an anthropometric measurement and serum protein levels which may be obtained easily and rapidly. The formula was applied to three groups of patients, firstly 106 patients undergoing major surgical resection, secondly to 16 patients admitted for minor surgery to assess a normal range, and thirdly 10 patients undergoing total parenteral nutrition. In patients undergoing major surgical resection the prognostic index was significantly greater in those patients developing complications than in the control group and a good predictor of the risk of complications. The index uses nutritional measurements to predict complications rather than being a measurement of nutritional status and is therefore a poor monitor of the efficacy of nutritional therapy.