The immunomodulatory effects of thalidomide on human immunodeficiency virus-infected children.

The safety and immune effects of low-dose thalidomide treatment (3 mg/kg/day for 28 days) were evaluated in a study involving 8 South African human immunodeficiency virus (HIV)-infected children. The children were 7-69 months old and in disease stages A1-C3. Thalidomide therapy did not affect virus load, even though none of the children was receiving antiretroviral therapy. Thalidomide stimulated CD8+ T cells in peripheral blood, which increased expression of the activation markers CD38 and human leukocyte antigen DR and of the memory cell marker CD45RO. The frequency of HIV gag-specific CD8+ T cells in peripheral blood increased in 3 of 4 children who were evaluated during treatment with thalidomide. Clinical adverse events were mild. In this study, thalidomide was found to be safe and well tolerated and caused significant immunomodulation at a low dose. This is the first report describing use of an oral drug that may enhance HIV-specific CD8+ T cell function in HIV-infected children.

Effect of amygdaloid kindling on rat striatal dopamine D1- and D2-receptors.

The effect of kindling on dopaminergic (DA) neurotransmission was assessed by measuring dopamine D1- and D2-receptor binding in the dorsal and ventral striatum of rats either 2 hours (short-term) or 3-4 weeks (long-term) after the last kindled seizure. Kindling did not have any significant long-term effect on DA D2-receptor Kd or Bmax values in the dorsal or ventral striatum or on DA D1-receptor parameters in the dorsal striatum. The short-term effect of kindled seizures was to abolish the asymmetry in DA D2-receptor density observed in the dorsal striatum of control rats. DA D1-receptor density was also increased in the dorsal striatum contralateral to the kindled amygdala of short-term rats. The short-term effects support the notion that limbic seizures can modify the lateral imbalance of DA activity in the striatum.

Prediction of amikacin dose requirements in neutropenic patients with haematological disease.

This study reports on the use of an easily applied Bayesian forecasting programme (OPT; Clydesoft) to predict amikacin dose requirements in 10 patients with haematological disease and neutropenic fever. OPT-determined dose adjustment achieved therapeutic drug levels for 80% of the peak and 94% of the trough measurements.

Effect of hypoxia on the hepatic metabolism of lidocaine in the isolated perfused pig liver.

The metabolism of lidocaine to monoethylglycinexylidide has been found useful as an indicator of liver function in association with liver transplantation. It has been postulated that this is due to the common effect of hypoxic damage on liver function and lidocaine metabolism. The effects of hypoxia on the elimination of lidocaine and the formation of monoethylglycinexylidide and on indexes of liver function were investigated with the isolated perfused pig liver preparation. This study was performed at similar hepatic effluent lidocaine concentrations of approximately 5 micrograms.ml-1 in normoxic (n = 7) and hypoxic (n = 8) livers of similar mass harvested from male Landrace x Large White pigs and perfused at standard unit hepatic flow rates. Whole blood lidocaine extraction ratio was 0.63 +/- 0.02 in normoxic livers (30% O2 at oxygenator inflow). It was significantly less (0.23 +/- 0.03) in livers subjected to hypoxia (2% O2 at oxygenator inflow), as were hepatic clearance (57.1 +/- 2.1 vs. 20.3 +/- 3.1 ml.min-1.100 gm-1), intrinsic clearance (1,706 +/- 182 vs. 284 +/- 53 ml.min-1.100 gm-1) and monoethylglycinexylidide formation as indicated by monoethylglycinexylidide/lidocaine ratios in the hepatic venous effluent (0.379 +/- 0.061 vs. 0.073 +/- 0.014) (p < 0.01). Hepatic oxygen consumption, adenine nucleotide status and bile flow were significantly impaired by hypoxia. Whereas perfusate potassium concentration increased early, AST levels showed delayed increases and ALT levels showed no changes. These changes correlated strongly with hepatic lidocaine elimination (p < 0.01). We conclude that lidocaine metabolism may be an early indicator of severe hepatic hypoxia.

Lidocaine decay and hepatic extraction in the pig.

Plasma lidocaine decay after injection was studied in five anaesthetized pigs and fitted to a two compartment open model. Derived pharmacokinetic parameters were employed to rapidly achieve plateau concentrations within 60 min of starting a two stage infusion of lidocaine hydrochloride. Hepatic extraction and clearance of lidocaine at steady state were determined in 10 pigs by transhepatic sampling and measurement of hepatic arterial and portal venous blood flow using perivascular ultrasonic flow probes placed at laparotomy. These data were compared with similar studies performed in man as well as the sheep, dog, monkey and cat. The lidocaine extraction ratio of 0.60 in the pig was found to be similar to that determined by others in man.

Effect of amygdaloid kindling on [3H]dopamine and [14C]acetylcholine release from rat prefrontal cortex and striatal slices.

The involvement of the dopaminergic (DA) systems in the control of limbic kindled seizures is ill defined. The effects of kindling on DA activity may have been overlooked in the past, because of its subtle unilateral occurrence and/or the variance of the endogenous imbalance of DA activity in normal animals. In the present study rats were screened for their endogenous DA imbalance using amphetamine-induced rotational behaviour. Electrical or sham kindling was applied in the hemisphere with the higher endogenous DA activity. Sections of the bilateral prefrontal cortex and dorsal and ventral striatum were dissected either 2 hours or 21 days after the final seizure and the electrically stimulated release of [3H]DA and [14C]acetylcholine (ACh) determined. Release was also measured in the presence of quinpirole or sulpiride to assess the activity of pre- and postsynaptic DA D2-receptors. Long-term effects of kindling consisted of facilitation of ACh release in the ventral striatum contralateral to the kindled amygdala and bilateral depression of DA release in the prefrontal cortex. Kindling therefore produced area specific changes in neurotransmitter systems giving rise to increased pro-convulsive cholinergic activity in the ventral striatum and decreased anti-convulsive dopaminergic activity in the prefrontal cortex.

Regional distribution of monoamines and dopamine D1- and D2-receptors in the striatum of the rat.

Dopamine (DA) D1- and D2-receptor densities were determined in 18 discrete areas of the caudate-putamen-globus pallidus of male Wistar rats and compared to local DA concentrations. All three parameters were found to decrease caudally. The globus pallidus was distinguished by the low concentration of DA and its receptors and high noradrenaline (NA) content. While there were no mediolateral differences in DA or DA D1-receptors, a clear mediolateral gradient was observed for DA D2-receptors which extended over several sections of the brain. The ratio of DA D1- to D2-receptors was significantly higher in the dorsal than in the ventral areas of the mediolateral and caudal striatum. This is the first report of clear dorsoventral differences in parameters relating to DA activity in the striatum. These findings may be of particular significance in understanding the functional dichotomy between the dorsal and ventral striatum.

Regional distribution of dopamine D1 and D2 receptors in the nucleus accumbens of the rat.

Dopamine (DA) D1 receptor density was found to be significantly lower in the rostral than in the medial and caudal areas of the nucleus accumbens. This roughly followed the distribution of DA terminals. The distribution of DA D2 receptors did not follow the DA terminal distribution. DA D2 receptor number was lower in the ventrorostral and higher in the dorsomedial area than in any other area of the nucleus accumbens.

Increased dopamine D2 receptor-mediated inhibition of [14C]acetylcholine release in the dorsomedial part of the nucleus accumbens.

Dopamine (DA) D2 receptor-mediated inhibition of the K+-stimulated release of [14C]acetylcholine (ACh) from prelabeled rat dorsomedial nucleus accumbens slices was found to be 1.7 times greater than that observed in dorsorostral and ventromedial slices. This observation is consistent with the 1.9 fold higher DA D2 receptor density found in the dorsomedial area. In contrast, there were no differences in the DA D2 receptor-mediated effects on [3H]DA release in these areas. In addition, DA D2 receptor-mediated effects on [3H]DA and [14C]ACh release could not be demonstrated in the ventrorostral part of the nucleus accumbens consistent with the fact that DA D2 receptors were barely detectable in this area. The results suggest that cholinergic terminals in the dorsomedial part of the nucleus accumbens are under greater inhibitory DA control than in other areas of the nucleus accumbens.

Lack of effect of chronic desipramine treatment on dopaminergic activity in the nucleus accumbens of the rat.

The binding of [3H]SCH 23390 to dopamine (DA) D1-receptors was measured in the nucleus accumbens of rats treated chronically with desipramine for 14 days. DA D1- and D2-receptor binding using [3H]SCH 23390 and [3H]spiperone, respectively as ligands, was determined in rats treated for 28 days. Neither Bmax nor Kd values were influenced by chronic desipramine treatment. In addition, chronic desipramine treatment (28 days) did not influence the dose dependent, quinpirole (10-1000 nM)-mediated inhibition of the electrically stimulated release of [3H]DA release and [14C]ACh from nucleus accumbens slices or the dose dependent increase in [3H]DA release and decrease in [14C]ACh release in the presence of 1 and 10 microM nomifensine. Therefore, our results suggest that the effect of chronic antidepressant treatment cannot be attributed to changes in either DA D1- or D2-receptor binding or DA D2-receptor function in the nucleus accumbens.

Effect of selective noradrenergic denervation on noradrenaline content and [3H]dopamine release in rat nucleus accumbens slices.

DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) treatment (50 mg/kg i.p., 10 days previously) significantly decreased the noradrenaline (NA) content of the rostral part of the nucleus accumbens. The medial and caudal areas were not affected. The nucleus accumbens appears to receive noradrenergic innervation predominantly from subcoeruleus nuclei of the pons-medulla while the locus coeruleus neurons project to the rostral area. The isoproterenol-induced enhancement of the K+-evoked release of [3H]dopamine (DA) was not affected by DSP4 treatment. Noradrenergic denervation does not appear to have been sufficient to cause up-regulation of postsynaptic beta-adrenoceptors.

Regional distribution of monoamines in the nucleus accumbens of the rat.

Monoamine concentrations were low in the rostral area of the nucleus accumbens. Their distributions were not identical. Differences were observed in the medial area. DA concentrations were high in both medial and caudal areas. Noradrenaline (NA) and serotonin (5-HT) concentrations were considerably lower than the dopamine (DA) concentration. The NA concentration was highest in the caudal area of the nucleus accumbens and the (5-HT) concentration was highest in the ventrocaudal area. There was a rostrocaudal decrease in the 3,4-dihydroxyphenylacetic acid (DOPAC)/DA and 5-hydroxyindole-3-acetic acid (5-HIAA)/5-HT ratios. Uptake of [3H]DA and [14C]choline was lowest in the rostral area. The K+-stimulated release of [14C]acetylcholine (ACh) was also lowest rostrally, but there was no rostrocaudal difference in the K+-stimulated release of [3H]DA. These results provide further evidence of the heterogeneity of the nucleus accumbens.

The elucidation of adrenal-cortical status by measuring two-hour urinary-free cortisol levels.

Urinary-free cortisol (UFC) measured in 24-h samples has provided unambiguous data regarding adrenal-cortical status, but collection is cumbersome and compliance is a problem. We reasoned that measuring UFC in 2-h samples collected at strategic times would distinguish patients with adrenal-cortical disorders from normal subjects. Patients with Cushing's syndrome demonstrated late P.M. (samples collected between 2000 and 2400 h) 2-h UFC levels that were greater than or equal to 12.0 micrograms/2 h (reference interval for this time period is 0.1-3.2 micrograms/2 h, n = 35). Several patients with various symptoms of Cushing's syndrome displayed late P.M. levels within the reference interval. Those with adrenal insufficiency had morning (collected between 0500 and 0900 h) levels less than or equal to 0.2 microgram/2 h (reference interval 1.7-21.2 micrograms/2 h, n = 37). These data indicate that adrenal-cortical status is reflected by measuring UFC levels in 2-h samples.