Pituitary abscess: a series of six cases

This study examined the influence of zopiclone, a third generation hypnotic, on the transition from slow wave sleep to paradoxical sleep (PS) which is increased at the expense of PS by barbiturates and benzodiazepines. The compound decreased sleep latency and increased the latency of the intermediate stage (IS) and PS at 2.5, 5 and 7.5 mg/kg IP. The amount of the IS was decreased because of the decrease in phase number up to 6 h at all doses. PS amount was decreased during 2 h at 2.5 mg/kg and during 4 h at 5 and 7.5 mg/kg also because of the decrease in phase number. The IS never substituted for PS. The IS spindle characteristics were not modified and the theta rhythm frequency slightly decreased at 5 mg/kg (IS) and 7.5 mg/kg (PS).     

Evaluation of copper sulfate and a copper lysine complex as growth promoters for weanling swine

Two 5-wk trials using 176 weanling pigs (average initial weight of 8.3 kg and age of 31 d) were conducted to examine the effect of feeding varying levels of dietary Cu from copper sulfate (CuSO4) or a copper lysine complex (CuLys) on performance, mineral stores, serum copper, and serum mitogenic activity. Dietary treatments were 0 (15 mg/kg of Cu in basal diet), 100, 150, or 200 mg/kg of supplemental Cu from CuSO4 or CuLys. Average daily gain and ADFI increased linearly (P < .01) with increasing dietary levels of Cu during wk 1 to 2, 3 to 5, and 1 to 5, with no difference (P > .10) between the Cu sources. Overall gain:feed ratios were not consistently affected by Cu source. Dietary Cu linearly increased liver, kidney (P < .001), and brain (P < .05) concentrations of Cu. In the liver, the linear response to supplemental Cu differed between Cu sources (P < .001); pigs fed 200 mg/kg of Cu from CuLys had the highest concentration of Cu. Serum Cu concentrations increased linearly during wk 1 to 2 (P < .01), 3 to 5, and 1 to 5 (P < .001), with no difference (P > .10) between sources. Serum mitogenic activity increased linearly during wk 1 to 2 and 1 to 5 (P < .05). Growth performance was linearly improved as the dietary level of Cu increased from 15 to 200 mg/kg, with similar responses for both Cu sources. Serum and tissue concentrations of Cu were generally equally affected by the two Cu sources, except liver Cu concentration, which was onefold higher for pigs fed 200 mg/kg of Cu as CuLys.     

Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors

PURPOSE: A phase I, multicenter trial of the thymidylate synthase (TS) inhibitor THYMITAQ (nolatrexed dihydrochloride; Agouron Pharmaceuticals, Inc, San Diego, CA) given by 5-day continuous infusion was performed to establish the maximum-tolerated dose (MTD) and to investigate pharmacokinetics, pharmacodynamics, and antitumor effects. METHODS: In vitro and in vivo preclinical studies demonstrated increased activity with prolonged nolatrexed exposure. In 32 patients, nolatrexed was given as a 5-day infusion at 96 to 1,040 mg/m2/d for 5 days. Pharmacokinetics were determined from high-performance liquid chromatography (HPLC) analyses of plasma and urine. In addition to studying toxicity, plasma deoxyuridine (UdR) elevations were measured as a marker of TS inhibition. RESULTS: The MTD was 904 mg/m2/d for 5 days and the recommended phase II dose is 800 mg/m2/d for 5 days. The dose-limiting toxicity was neutropenia with clinically significant thrombocytopenia and mucositis. These antiproliferative toxicities of nolatrexed were predictable and reversible. A partial response that lasted 3 months occurred in a patient with metastatic colorectal cancer. Pharmacokinetics were nonlinear, with the median plasma clearance (CI) decreasing from 151 mL/min/m2 (range, 124 to 211) at 96 mg/m2/d for 5 days to 49 mL/min/m2 (range, 30 to 84) at 768 mg/ m2/d for 5 days. The half-life (t1/2) was 173 minutes (range, 43 to 784) and 18% (range, 9% to 35%) of the dose was excreted unchanged in the urine. Plasma UdR increased, but returned to pretreatment levels after the end of infusion. Hematologic toxicity was significantly related to nolatrexed plasma concentrations and dose. CONCLUSION: Nolatrexed can be safely administered to patients at a dose of 800 mg/m2/d over 5 days by continuous intravenous infusion and this schedule is associated with antitumor effects. The phase II evaluation of nolatrexed is ongoing.     

Tissue specificity and mechanism of vitamin D receptor up-regulation during dietary phosphorus restriction in the rat

Dietary phosphorus restriction up-regulates intestinal vitamin D receptor (VDR), but the tissue specificity of the up-regulation and the mechanism of receptor accumulation remain unknown. Therefore, the effects of low phosphorus diet (LPD) on VDR content in intestine, kidney, and splenic monocytes/macrophages were examined. Male Sprague-Dawley rats weighing 50-100 g were fed a normal diet (NPD; 0.6% Ca, 0.65% P) as controls followed by an LPD (0.6% Ca, 0.1% P) for 1-10 days (D1-D10). LPD rapidly decreased serum P levels by D1 from 11.11 +/- 0.19 mg/dl (mean +/- SE) to 4.98 +/- 0.37 mg/dl (n = 9). LPD increased total serum Ca from 10.54 +/- 0.09 mg/dl to 11.63 +/- 0.15, 12.17 +/- 0.15, and 12.39 +/- 0.18 mg/dl by D1, D2, and D3, respectively, and then remained stable. Serum 1,25-(OH)2D3 rapidly increased from 123 +/- 5.4 pg/ml to 304 +/- 35 pg/ml by D1, reached a plateau through D5, and then gradually increased to 464.9 +/- 27.7 pg/ml by D10. Intestinal VDR quantitated by ligand binding assay increased 3.5-fold from 169.6 +/- 13.7 fmol/mg of cytosol protein in rats fed NPD (n = 12) to a peak of 588.3 +/- 141.88 fmol/mg of protein by D3 (n = 6; p < 0.001) and then decreased to a plateau level of 2.5-fold greater than NPD (p < 0.05) during D5 to D10. In contrast, LPD did not up-regulate kidney or splenic monocyte/macrophage VDR. Northern blot analysis showed that intestinal VDR mRNA increased 2-fold by D2 (n = 3) of LPD and then gradually decreased to control levels after D5. In contrast, kidney VDR mRNA levels did not change during the first 5 days of P restriction and then subsequently decreased to 50% of NPD controls. The results of these studies indicate that VDR up-regulation during dietary phosphorus restriction is tissue-specific and that the mechanism of the up-regulation is time-dependent. Acutely (D1-D5), phosphorus restriction up-regulates intestinal VDR through increased VDR gene expression, whereas chronic (D5-D10) phosphorus restriction appears to alter VDR metabolism through nongenomic mechanisms that are consistent with prolongation of the half-life of the receptor. The nature of the tissue-specific regulation of VDR during phosphorus restriction remains to be determined.     

Dexamethasone-induced hypertension in the rat: effects of L-arginine

1. The effects of L-arginine treatment on dexamethasone-induced hypertension were examined in the Sprague-Dawley rat. Seventy rats were randomly divided into the following eight groups: sham, dexamethasone (5 and 10 micrograms/day, L-arginine (100 and 500 mg/kg per day), L-arginine (100 or 500 mg/kg per day) + dexamethasone (10 micrograms/day), L-arginine (520-797 mg/kg per day in food) + dexamethasone (5 micrograms/day). Systolic blood pressure (SBP), bodyweight and plasma nitrate/nitrite concentration were measured. 2. Dexamethasone (5 and 10 micrograms/day) increased SBP in both sham and L-arginine-treated rats. Dexamethasone at 10 micrograms/day decreased bodyweight, but did not alter plasma nitrate/nitrite concentrations. 3. L-Arginine (500 mg/kg per day, i.p.) increased plasma nitrate/nitrite concentrations in 10 micrograms/day dexamethasone-treated rats. L-Arginine did not alter blood pressure in either sham or dexamethasone-treated rats. 4. Dexamethasone-induced hypertension differs from adrenocorticotropic hormone (ACTH)-induced hypertension in the rat in that it is not modified by L-arginine. Thus, ACTH-induced hypertension cannot be explained simply in terms of glucocorticoid activity.     

Medicine in the vocal arts

The effects of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) on the central nervous system (CNS) were studied in rats. Behavioural and neurochemical studies were performed. Results show that acute and oral administration of dimethylamine 2,4-D was able to decrease locomotion and rearing frequencies and to increase immobility duration of rats observed in an open-field test. Treatment of rats with p-chlorophenylalanine (PCPA) was unable to change rat's open-field behaviour; 5-hydroxytryptophan (5-HTP) administration not only increased locomotion and rearing frequencies but also decreased immobility duration. Pretreatment of the rats with PCPA and 5-HTP decreased and increased dimethylamine 2,4-D effects, respectively. The herbicide was not able to change the striatal levels of dopamine and homovanilic acid but decreased the striatal levels of serotonin (5-HT), as observed for the doses of 100 and 200 mg/kg and increased those of 5-hydroxyindoleacetic acid (5-HIAA) as measured after the 200 mg/kg dose treatment. When the levels of serotonin and 5-HIAA were measured at the brain stem level, only those of 5-HIAA were modified, being increased by diethylamine 2,4-D (60; 100 and 200 mg/kg); this increment on 5-HIAA levels was observed even 1 hr after pesticide administration. Further analysis showed that 2,4-D concentrations chromatographically detected both in serum and brain of the intoxicated animals were dose-dependent, being found as early as 1 hr after the smaller dose of the herbicide used (10 mg/kg). The results suggest that diethylamine 2,4-D modify 5-HT functional activity within the CNS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary results and long-term outcome of an ambulatory, cardiac rehabilitation model (phase II) after myocardial infarct, dilatation treatment and heart operation

From October 1994 to July 1996, 128 patients (30 women, 98 men) participated in an outpatient cardiac rehabilitation program (phase II). Our objectives were to demonstrate risk-factor modification and increased work-load capacity resulting directly from the rehabilitation in terms of primary results and long-term effects, 6 months (n = 59) and 12 months (n = 30) after termination of the program. We observed how many of the patients were able to be occupationally re-integrated after completion of phase II rehabilitation. During the 4-week program, the work-load capacity increased significantly from 1.2 W/kg to 1.5 W/kg (p < or = 0.05). After 6 months (1.4 W/kg) and 1 year (1.5 W/kg), consistently high workload capacities were noted. Total cholesterol decreased significantly from 247 mg/dl to 201 mg/dl (p < or = 0.05) during the 4-week program. After 6 months (219 mg/dl) and 1 year (210 mg/dl) significant reductions persisted (p < or = 0.05). Similar results with LDL-cholesterol were seen: 185 mg/dl before entering the program, 146 mg/dl after 4 weeks, 158 mg/dl after 6 months and 151 mg/dl after 1 year. Triglyceride levels showed a significant reduction (p < or = 0.05), 189 mg/dl before entering in the program, 148 mg/dl after 4 weeks, 143 mg/dl after 6 months, and 135 mg/dl after 1 year. The HDL-levels increased slightly as a long-term effect, i.e., from 51 mg/dl to 49 mg/dl during the 4 week program, and 57 mg/dl after 6 and 12 months. Of the patients questioned (n = 73), 73% found the program very good, 27% said it was good, and no patient was dissatisfied. Of the 63 patients who were actively employed before becoming ill and later entered our program, 51 (81%) were able to be immediately re-integrated into their previous occupation. In several cases this re-integration took 7 weeks. Seven (11%) patients applied for pension, and 5 (8%) patients remained unemployed on sick-leave.     

Abdominal non-Hodgkin''s lymphoma in childhood

Effect of 3, 4-dihydroxyphenylserine (DOPS), a norepinephrine precurosr, on harmaline tremor was investigated in mice to elucidate the role of norepinephrine in the genesis of tremor. 1) Spontaneous motor activity was inhibited by L-threo-DOPS (200 mg/kg i.p.). 2) Tremor induced by harmaline (5 and 7 mg/kg i.p.) was enhanced by alpha-methyl-p-tyrosone (200 mg/kg i.p.). 3) The development and duration of tremor induced by harmaline (10 mg/kg i.p.) were inhibited significantly in a dose dependent manner by L-threo-DOPS (50, 70, 100, 150 and 200 mg/kg i.p.), but neither by D-threo-DOPS (200 mg/kg i.p.) nor DL-erythro-DOPS (200 mg/kg i.p.). 4) L-threo-DOPS (200 mg/kg i.-.) had no effect on the development of tremor induced by tremorine (5 and 10 mg/kg i.p.), while lacrimation and diarrhea caused by tremorine was markedly inhibited. 5) Administration of harmaline (10 mg/kg i.p.) produced an increase in brain 5-hydroxytryptamine content but not in that of norepinephrine. Administration of L-threo-DOPS (100 mg/kg i.p.) increased the norepinephrine content but not the 5-hydroxytryptamine content in the brain. Inhibition of harmaline tremor induced by L-threo-DOPS is attributed to the L-norepinephrine converted from L-threo-DOPS and the involvement of a noradrenergic mechanism in harmaline tremor has to be considered.     

Effects of mesulergine treatment on diet selection, brain serotonin (5-HT) and dopamine (DA) turnover in free feeding rats

1. The effects of mesulergine, a 5-hydroxytryptamine (5-HT) receptor antagonist with dopamine (DA) agonistic properties, on rats diet selection over a seven day period and on 5-HT and DA turnover was studied. 2. Three groups of male Wistar rats were individually caged and ad libitum fed with a standard (SD) and 50% sweet carbohydrate enriched diet (CED). Food intake was measured daily 4 hrs and 24 hrs after i.p. injections of mesulergine (1 and 3 mg/kg) or vehicle. 5-HT and 5-HIAA in hypothalamus (Hy), Striatum (St) and hippocampus (Hi) as well as DA and DOPAC in (Hy) and (St) were assayed at the 8th day of the experiment. 3. There was a dose dependent increase of SD consumption 4 hrs after mesulergine treatment while the CED remained unchanged with total food intake dose dependently increased as a consequence. At 24 hrs measurements SD consumption was increased only for the dose of 1 mg/kg of mesulergine, while a dose dependent decrease of CED intake was observed. Total food intake was unchanged for the dose of 1 mg/kg and decreased with the dose of 3 mg/kg consequently. A dose dependent decrease of rats body weight was observed too. 4. A significant increase of 5-HIAA/5-HT ratio in (Hy) and (St) for the dose of 1 mg/kg and in (Hi) for the dose of 3 mg/kg with no changes of DA turnover were found. 5. The above data suggest a dual mode of action of mesulergine presented as a short term hyperphagia due to simultaneous antiserotonergic and dopaminergic activity and long-term hypophagia due to long-term agonistic effects of dopaminergic neurons.     

Development of a homologous radioimmunoassay for mouse growth hormone receptor

A RIA for mouse GH receptor (mGHR) was developed. A synthetic peptide corresponding to the carboxyl-terminal 14 amino acids of the mGHR (GHR-2 peptide) was used as the antigen for antiserum production. The synthetic peptide was also used as the standard and radioligand in the RIA. The ability of the antiserum to recognize the mGHR was demonstrated by quantitating receptor concentrations in liver and mammary gland from virgin and 15-day-pregnant mice. Serial dilutions of these samples yielded displacement curves parallel to the synthetic peptide. No significant cross-reactivity was seen with serum from virgin or 15-day-pregnant mice, mGH, recombinant mGH-binding protein (mGHBP), a synthetic peptide identical to the hydrophilic tail of mGHBP, or a 14-amino acid synthetic peptide corresponding to amino acids 338-351 of mGHR (GHR-1 peptide). The concentration range of the mGHR RIA was 0.5-200 nM, and the intra- and interassay coefficients of variation were 6.5% and 6.1%, respectively. The concentration of liver GHR increased significantly during pregnancy compared with that in virgin mice, from 0.246 +/- 0.045 pmol/mg protein (mean +/- SEM; n = 5) in the virgin animals to 1.015 +/- 0.159 pmol/mg protein (n = 5) in pregnant mice. In contrast, the mGHR concentration in the mammary gland decreased significantly during pregnancy from 0.606 +/- 0.201 pmol/mg protein (mean +/- SEM; n = 5) to 0.299 +/- 0.027 pmol/mg protein (n = 5). Comparison of the total number of binding sites in livers from virgin and pregnant mice using the GH RRA and the combined results of the mGHR and mGHBP RIAs showed that the two methods gave almost identical results for livers from virgin animals, or 0.363 +/- 0.063 pmol/mg protein (mean +/- SEM; n = 3) and 0.371 +/- 0.008 pmol/mg protein (n = 3) for the GH RRA and the mGHR plus mGHBP RIAs, respectively. However, in livers from pregnant animals, the combined results from the mGHR and mGHBP RIAs were approximately 1.8 times higher than those obtained by the GH RRA, or 6.732 +/- 0.612 pmol/mg protein (mean +/- SEM; n = 3) and 3.693 +/- 0.67 pmol/mg protein (n = 3) for the mGHR plus the mGHBP RIAs and the GH RRA, respectively. The increase in the total GH binding capacity in livers from pregnant mice compared with those from virgin animals was largely due to an increase in the GHBP content. The increase in GHR was only 2.4-fold, or from 0.153 +/- 0.01 pmol/mg protein (mean +/- SEM; n = 3) in virgin mice to 0.364 +/- 0.03 pmol/mg protein (n = 3) in the 15-day-pregnant mice, whereas GHBP increased almost 30-fold during pregnancy, or from 0.218 +/- 0.003 pmol/mg protein (mean +/- SEM; n = 3) in virgin animals to 6.369 +/- 0.607 pmol/mg protein (n = 3) in pregnant mice.     

Biphasic effects of typical antidepressants and mianserin, an atypical antidepressant, on aggressive behavior in socially isolated mice

Effects of several typical antidepressants and of an atypical antidepressant, mianserin, on the aggressive behavior (AGB) in long-term isolated mice were examined. IP administration of maprotiline (2.5 and 5 mg/kg), amitriptyline (5 and 10 mg/kg), clomipramine (2.5 and 5 mg/kg), and mianserin (5 mg/kg) significantly increased the duration of AGB. However, at higher doses (maprotiline, 10 mg/kg; amitriptyline, 20 mg/kg; clomipramine, 10 and 20 mg/kg; mianserin, 10 and 20 mg/kg) these antidepressants either did not affect AGB or inhibited it. Amitriptyline (20 mg/kg) and mianserin (10 mg/kg) but not maprotiline (10 mg/kg) or clomipramine (20 mg/kg) decreased spontaneous motor activity in isolated mice. Yohimbine (0.5 mg/kg, IP), an alpha 2-antagonist, changed the antidepressant-induced enhancement of AGB into inhibition without affecting the basal aggressive responses. Prazosin (0.3 mg/kg, IP), an alpha 1-antagonist, did not affect either maprotiline- or clomipramine-induced enhancement of AGB, but it changed the mianserin-induced enhancement of AGB into inhibition. These results indicate that antidepressants that inhibit noradrenaline uptake and/or stimulate noradrenaline output from nerve terminals have biphasic effects on AGB in isolated mice and that the antidepressant-induced enhancement of AGB is mediated by noradrenergic stimulation of alpha 2-adrenoceptors, whereas the antidepressant-induced inhibition of AGB may be mediated by non-alpha 2-adrenoceptors or by nonadrenergic system(s).     

Compensatory sleep responses to wakefulness induced by the dopamine autoreceptor antagonist (-)DS121

The effect of the dopamine autoreceptor antagonist (-)DS121 on wakefulness, locomotor activity, body temperature and subsequent compensatory sleep responses was examined in the rat. Animals entrained to a light-dark cycle were treated at 5 h after lights-on (CT-5) with 0.5, 1, 5 or 10 mg/kg i.p. (-)DS121 or methylcellulose vehicle. An additional group received 5 mg/kg i.p. (-)DS121 or vehicle 6 h after lights-off (CT-18). At CT-5, (-)DS121 dose-dependently increased wakefulness, locomotor activity and body temperature, and decreased both non-rapid eye movement sleep (NREM) and rapid eye movement sleep (REM) during the first 4 h post-treatment relative to vehicle controls. REM interference lasted up to 3 h longer than NREM. Low doses of (-)DS121 (0.5 and 1 mg/kg) produced relatively little waking that was not followed by significant compensatory sleep responses. In contrast, higher doses (5 and 10 mg/kg) produced compensatory hypersomnolence (robust increases in NREM immediately after the primary waking effect) that was proportional to the duration of drug-induced wakefulness. NREM recovery 24 h post-treatment was the same for the 5 mg/kg (65.4 +/- 9.9 min) and 10 mg/kg (64.8 +/- 9.3 min) doses, but was not proportional to prior wake duration. NREM displaced by drug-induced wakefulness was recovered completely by 24 h post-treatment at the 5 mg/kg dose, but only 63.5% recovered at 10 mg/kg. In contrast, equivalent wakefulness produced by sleep deprivation yielded 100% NREM recovery. At CT-18, (-)DS121 (5 mg/kg) increased wakefulness without disproportionately increasing locomotor activity, and was compensated fully by 24 h post-treatment. These data show that (-)DS121 dose-dependently increases wakefulness, which is followed by hypersomnolence that is proportional to drug-induced wake-promoting efficacy.     

Phase I clinical and pharmacological studies of benzylacyclouridine, a uridine phosphorylase inhibitor

Benzylacyclouridine (BAU, IND 039655) is a potent and specific inhibitor of uridine phosphorylase (UrdPase; EC 2.4.2.3). This enzyme plays a major role in regulating uridine homeostasis and also catalyzes the conversion of fluoropyrimidine nucleosides to their respective bases. Inhibition of UrdPase enzyme activity 18-24 h after 5-fluorouracil (5-FU) administration increased plasma levels of uridine and enhanced the therapeutic index of 5-FU by rescuing normal tissues. Moreover, in vitro preclinical studies have also shown that inhibiting UrdPase enzyme activity by BAU prior to administration of 5-FU increased cytotoxicity in a number of human cancer cell lines. A series of preclinical studies was performed in dogs and pigs to evaluate the pharmacological and pharmacodynamic properties of BAU. These data showed a sustained elevation in plasma uridine concentration in both animal models. The rapid degradation of a tracer dose of uridine into uracil was virtually arrested by BAU administered both p.o. or i.v. The t1/2 of BAU was 1.8-3.6 h in dogs, with bioavailability levels of 85% (30 mg/kg) and 42.5% (120 mg/kg). In pigs, the half-life varied from 1.6 to 2.3 h, with a bioavailability of 40% at 120 mg/kg. The drug was distributed into most tissues with a tissue: plasma ratio of approximately 0.7. On the basis of these preclinical studies, we performed a Phase I clinical trial of BAU in patients with advanced cancer. Patients received 200, 400, 800, and 1600 mg/m2 BAU as a single oral dose. Toxicities included grade 2 anemia, grade 1 fever, grade 1 fatigue, grade 1 constipation, and grade 1 elevation in alkaline phosphatase; none of these toxicities were observed to be dose dependent. The maximum tolerated dose and dose-limiting toxicity were not reached at the doses given. BAU plasma concentrations and area under the curve correlated linearly with the oral dose level. The pharmacokinetics of BAU were consistent with a first-order clearance, with average peak concentrations ranging from 19 microM (200 mg/m2) to 99 microM (1600 mg/m2) and tbeta1/2 ranging from 3.0 to 3.9 h at the four dose levels. Compared with baseline plasma uridine, treatment of patients with 200, 400, 800, and 1600 mg/m2 BAU increased peak uridine concentrations by 120, 150, 250, and 175%, respectively. On the basis of this clinical study, the suggested Phase II starting dose of BAU in combination with 5-FU is 800 mg/m2. Studies combining BAU with 5-FU and incorporating appropriate molecular and biochemical end points to assess the effects of this drug combination on tumor and/or surrogate tumor tissue are under way.     

Changes in dopamine, serotonin and their metabolites in discrete brain areas of rat offspring after in utero exposure to cocaine or related drugs

The concentrations of dopamine (DA), serotonin (5HT) and their metabolites were quantified in 5 brain areas of rats exposed to saline, cocaine (15 mg/kg b.i.d.), amitriptyline (10 mg/kg), or amfonelic acid (AFA, 1.5 mg/kg) throughout gestation. Male pups from 3 similarly treated dams were fostered to 2 surrogate dams. The process of breeding and rearing was repeated 4 times with new dams to build the groups to 4-12, since only one pup per litter was used for any one measurement. AFA was used to mimic the dopamine (DA) uptake blockade and stimulant properties of cocaine and amitriptyline was used to mimic the other pharmacological effects of cocaine. At postnatal days (PND) 30, 60, and 180, one pup per litter was removed for HPLC analysis of monoamines. A second pup received 0.3 mg/kg haloperidol, catalepsy assessed after 1 hr, and the brain used for analysis. The cataleptic response to haloperidol was unaffected by any prenatal treatment. The striatum from PND 30 cocaine rats had decreased levels of DA without a decrease in DA metabolites. At PND 60 in cocaine exposed rats, DA and DOPAC concentrations were increased, and 5HT levels were decreased in the striatum. The amitriptyline-exposed group exhibited decreased 5HT and 5-HIAA levels in the striatum. The hypothalamus of the cocaine group had lower levels of 5-HIAA, and other brain areas had a trend for lower levels of 5HT and 5-HIAA. At PND 180, DOPAC was increased in the striatum and prefrontal cortex of the cocaine group. Haloperidol-induced altered monoamine metabolism was unaffected by any prenatal treatment at any age. These data suggest that age-related changes in the DA and 5HT neurotransmission systems occur in rats exposed prenatally to cocaine. However, the ability of the dopaminergic system to respond to a challenge by a DA receptor blocker is unaltered by these in utero treatments.     

The role of dopaminergic and serotonergic mechanisms in the development of swimming ability of young rats

Neonatal swimming behavior was studied after a single subcutaneous injection of L-dopa methyl ester (50 mg/kg; 200 mg/kg) apomorphine (0.1 mg/kg; 1.0 mg/kg), DL-amphetamine (0.5 mg/kg; 10 mg/kg), haloperidol (0.5 mg/kg; 1.0 mg/kg), L-tryptophan (50 mg/kg; 100 mg/kg), methysergide (1.0 mg/kg; 5.0 mg/kg) as well as intraventricular injection of 100 microgram 6-OHDA. 1-, 3-, 5- and 7-day-old rats were placed into a temperature-controlled aquarium (37 degrees C) and the pattern of motor coordination, latency time to swimming (LTS) and the number of foreleg strokes for 10 s (FS) were measured. When compared to the physiological saline-injected controls, rats that received L-dopa showed a striking increase of FS at all ages but the most striking improvement of motor coordination was found in newborn rats. On day 1 both doses of DL-amphetamine induced increases in FS and improvement of motor coordination, whereas apomorphine failed to show any effect at this age. On days 3, 5 and 7 low doses of DL-amphetamine and apomorphine increased the FS. However, high doses resulted in a decrement in swimming performance. Haloperidol impaired swimming on day 1 but produced a significant increase of FS on days 5 and 7. Neonatal injection of 6-OHDA delayed development of motor coordination, reduced FS and increased LTS. On days 3, 5 and 7 high doses of L-tryptophan elicited an increase of FS, while high doses of methysergide caused significant impairment of performance. It is suggested that the brain rapidly converts the administered L-dopa to dopamine during the first week of life and there appears to be a strong dependent relationship between the pattern of motor coordination and the amount of available dopamine in the developing brain.     

MDMA ('Ecstasy') enhances 5-HT1A receptor density and 8-OH-DPAT-induced hypothermia: blockade by drugs preventing 5-hydroxytryptamine depletion

One week after a single administration of 3,4-methylenedioxymethamphetamine (MDMA HCI, 30 mg/kg i.p.), 5-HT1A receptor density was significantly increased by approximately 25-30% in the frontal cortex and hypothalamus of rats. The increased density correlated with the potentiation of the hypothermic response to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1 mg/kg s.c.). Hypothalamic 5-HT7 receptors, which also bind 8-OH-DPAT, were not changed, however, by MDMA. Fluoxetine (5 mg/kg s.c.), ketanserin (5 mg/kg s.c.) or haloperidol (2 mg/kg i.p.), given 15 min prior to MDMA, prevented the depletion of 5-hydroxytryptamine (5-HT) induced by MDMA and also blocked the effects of this neurotoxin on 5-HT1A receptor density and on 8-OH-DPAT-induced hypothermia. The protection afforded by drugs against 5-HT loss did not correlate, however, with the antagonism of the acute hyperthermic effect of MDMA. The present results indicate that drugs able to prevent or to attenuate MDMA-induced 5-HT loss also prevent the changes in 5-HT1A receptor density as well as the enhanced hypothermic response to the 5-HT1A receptor agonist 8-OH-DPAT in MDMA-treated rats.     

Peripheral vascular versus direct cardiac effects of calcium

Peripheral vascular and direct cardiac effects of calcium chloride were determined in a new animal model, the unanesthetized calf, before and after replacement of its natural heart (NH) with a pneumatically driven artificial heart (AH). Calcium (5 and 10 mg/kg) significantly increased cardiac output (Qt) and reduced systemic vascular resistance (SVR) before and after AH implantation. Increases in Qt in AH calves and reductions in SVR in both NH and AH calves were, however, transient, being present 5 minutes but not 15 minutes after both doses of calcium. Increases in Qt and reductions in SVR were significantly (P less than .05) greater after 10 mg/kg than after 5 mg/kg calcium in NH and AH calves. Both doses of calcium produced greater (P less than .05) increases of Qt in NH than in AH animals but similar reductions in SVR. Pulmonary vascular resitance, heart rate and pulmonary arterial and right atrial pressures were not significantly altered by either dose of calcium in NH or AH calves. Mean aortic pressure was influenced by 10 mg/kg calcium only, being transiently reduced in AH calves and increased in NH animals. Pulmonary shunt (QS/Qt) was increased by both doses of calcium in NH calves but only by 10 mg/kg in AH animals. Correlations of mean change in QS/Qt with mean change in Qt were high both before (r=.99) and after (r=.97) AH implantation. These data demonstrate that calcium significantly reduces SVR in a dose-related manner as well as exerting a positive inotropic effect on the myocardium.     

Differential effects of chronic antidepressant treatment on swim stress- and fluoxetine-induced secretion of corticosterone and progesterone

Hypersecretion of cortisol occurs in numerous patients with major depression and normalizes with clinical recovery during the course of chronic antidepressant treatment. These clinical data suggest that investigation of the effects of antidepressant treatments on the regulation of the brain-pituitary-adrenal axis may assist in elucidating the therapeutic basis of antidepressant actions. In the present investigation, both swim stress and acute fluoxetine challenge increased release of corticosterone and progesterone to reflect an activation of the brain pituitary-adrenal axis. The effects of chronic antidepressant treatment (21 days) on corticosterone and progesterone secretion induced by these challenges were investigated. Chronic fluoxetine treatment (5 mg/kg/day) completely blocked the increased secretion of corticosterone and progesterone in response to the acute fluoxetine challenge. Chronic treatment with desipramine, imipramine or amytriptyline (15 mg/kg/day) also markedly attenuated fluoxetine-induced corticosterone and progesterone secretion. However, chronic treatment with the monoamine oxidase inhibitors, phenelzine (5 mg/kg) and tranylcypromine (5 mg/kg), did not affect this hormonal response to acute fluoxetine challenge. Plasma levels of fluoxetine after acute challenge were not significantly different for the various chronic antidepressant treatment conditions from the chronic saline controls; therefore, an increase in the metabolism of fluoxetine can not explain the antagonism of the fluoxetine-induced hormonal response after chronic antidepressant treatment. In contrast to the effects of selected antidepressants on acute fluoxetine-induced steroid release, chronic treatment with imipramine (20 mg/kg/day), fluoxetine (5 mg/kg/day) or phenelzine (5 mg/kg) did not significantly alter this swim stress-induced corticosterone or progesterone secretion. Because chronic fluoxetine and tricyclic antidepressant drugs blocked the acute action of fluoxetine to increase adrenal cortical secretion, but did not alter swim stress-induced secretion of these steroids, we propose that distinct neurochemical mechanisms control fluoxetine and swim stress-induced steroid release. We speculate that the substantial adaptive response to those chronic antidepressant treatments, which minimize the effect of acute fluoxetine challenge to increase in corticosterone and progesterone secretion, may be relevant to the therapeutic actions of these drugs.     

Cyclosporine protects glomeruli from FSGS factor via an increase in glomerular cAMP

Cyclosporine (CsA) administration to patients with recurrent focal segmental glomerulosclerosis (FSGS) after transplantation results in remission of proteinuria. We have shown that sera from patients with recurrent FSGS can increase the glomerular albumin permeability (Palbumin) and that increase in glomerular cAMP levels can alter the permeability characteristics of glomeruli in vitro. The purpose of this study was to determine if the increased glomerular levels of cAMP were related to the protective effects of CsA on an increase in Palbumin by FSGS sera. Glomeruli from Sprague-Dawley rats following intraperitoneal administration of CsA (25 mg/kg/day), cremophore (25 mg/kg/day), or saline for 5 days were incubated with 1:50 dilution of serum from three FSGS patients or with pooled normal human serum prior to calculation of Palbumin. Glomerular cAMP was measured by radioimmunoassay. Glomerular ultrastructural changes were assessed by transmission electron microscopy (TEM). Serum from three FSGS patients markedly increased Palbumin of glomeruli from saline or cremophore treated rats (saline, 0.68+/-0.08; 0.72+/-0.07; 0.70+/-0.07; and cremophore, 0.79+/-0.05; 0.81+/-0.02; 0.79+/-0.01; n=25 glomeruli in each group). In contrast Palbumin of glomeruli from CsA treated rats was not increased by any of the three FSGS sera tested (0.03+/-0.02; 0.04+/-0.05; 0.02+/-0.07, n=25 glomeruli in each group). Glomerular cAMP (pmol/mg of protein) increased 5 fold in CsA treated rats (328+/-26; 5 rats) compared with cremophore or saline treated rats (87+/-24 and 65+/-23, P<0.01; 5 rats in each group). The glomerular basement membrane appeared to be thickened and the lamina densa had an irregular appearance after treatment with CsA. No ultrastructural changes of glomerular epithelial or endothelial cells were evident. We conclude that CsA may have a direct protective effect on the glomerular filtration barrier in FSGS. We postulate that increased levels of glomerular cAMP by CsA may play an important role in protecting the glomerular Palbumin effect of the FSGS factor and may contribute to remission of proteinuria in FSGS patients.     

Modeling a Combined Anaerobic/Anoxic Oxide and Rotating Biological Contactors Process under Dissolved Oxygen Variation by Using an Activated Sludge-Biofilm Hybrid Model

A hybrid model which incorporated a biofilm model into the general dynamic model was developed to predict the effluent quality of a combined activated sludge and biofilm process—Taiwan National Central University Process 1. The system was performed under three different dissolved oxygen (DO) conditions in the oxic tank, including 2.0, 1.0, and 0.5 mg/L. When the DO increased from 0.5 to 2.0 mg/L, the soluble biodegradable substrate (SS) and soluble phosphate (PO4) in the effluent were not significantly influenced. Their removal efficiencies were above 92 and 94%. Ammonia–nitrogen (NH3) removal efficiency increased from 36 to 83% and nitrate–nitrogen (NO3) increased from 1.7 to 2.9 mg/L. In biofilm, when the DO was 2.0 mg/L, the active autotrophic biomass (ZA) fraction was 15.7% (surface) to 12.9% (substratum). But when the DO was 0.5 mg/L, the ZA fraction became lower and the fraction was 6.2% (surface) to 3.5% (substratum). The fraction of active nonpoly-P heterotrophic biomass (ZH) in the biofilm did not vary significantly, the values were about 28–35%. ZI decreased as the DO increased. SS in the biofilm did not vary significantly and was maintained at about 2.0 mg/L. When DO increased, NO3 also increased, NH3 decreased from 13.1 to 1.8 mg/L in biofilm.