The desipramine-induced growth hormone response and the dexamethasone suppression test in obsessive-compulsive disorder.

Ten patients with DSM-III-R obsessive-compulsive disorder (OCD) underwent the desipramine (DMI) growth hormone (GH) stimulation test as well as the dexamethasone suppression test (DST). The results were compared with the responses in a group of matched healthy controls. The GH response to DMI did not differ between patients and controls and 9 of 10 patients showed cortisol suppression in response to dexamethasone. The data suggest that neither alpha 2 adrenergic dysfunction nor DST non-suppression are features of primary OCD.     

The pitfalls of the dexamethasone suppression test: A biological marker of endogenous depression?

In the past few years there have been numerous publications which have stressed the value of the dexamethasone suppression test (DST) as a diagnostic marker of endogenous depression. Our own studies in 333 psychiatric inpatients and 121 healthy subjects did not reveal a differential diagnostic use for the DST. This result is in good agreement with other results in the literature. Our data demonstrate that intervening variables such as severity of illness, weight loss, sleep disturbances, situational stress, drug and alcohol withdrawal, and the pharmacokinetics of dexamethasone have an important influence on DST results, regardless of the diagnostic classification.     

Dexamethasone in the treatment of meningeal leukemia

To determine if dexamethasone has a role in the treatment of meningeal leukemia, 8 consecutive patients with acute lymphoblastic and signs or symptoms of CNS were included in the study. After the confirmation of leukemic blast cells on cerebrospinal fluid, they received intrathecal and IV dexamethasone; 3 days later the patients received “triple” intrathecal chemotherapy with dexamethasone, methotrexate and cytarabine, and the spinal fluid was studied again. All patients had good clinical response and 7 out of the 8 patients showed reduction on the CSF cell count after the use of dexamethasone alone. The results suggest that dexamethasone is a lympholytic agent that could play a more active role in the prevention and therapy of meningeal leukemia and should be preferred over hydrocortisone in the so called “triple” intrathecal chemotherapy for the prevention and treatment of CNS leukemia. © 1995 Wiley-Liss, Inc.     

Catabolic effect in premature infants with early dexamethasone treatment

To evaluate the catabolic effects of dexamethasone therapy on protein metabolism, amino acid concentrations and urinary 3-methylhistidine (3MH) were measured in 28 premature infants who were included in a double-blind controlled study using early dexamethasone therapy in the prevention of bronchopulmonary dysplasia. Fifteen infants received dexamethasone (0.5mg/kg/day i.v.) and 13 infants received normal saline as control. Heparinized venous blood samples for amino acid analysis were obtained before the study and again at day 5 after starting the study. Urinary 3MH was measured on days 1, 3, 5, 7, 14, 21, and 28 of treatment. A substantial increase in amino acid concentrations was observed in infants receiving dexamethasone. Alanine, glutamine, citrulline, ornithine and cystine concentrations increased twofold or more. The 3MH:creatinine ratio was increased in the treated group. These metabolic effects were most likely due to an increase in protein catabolism.     

Ex vivo stimulation of cord blood mononuclear cells by dexamethasone and interleukin-7 results in the maturation of interferon-gamma-secreting effector memory T cells

The effects of dexamethasone phosphate and interleukin‐7 upon the proliferation of T‐cells and the production of interferon‐γ in the newborn's cord blood mononuclear cell cultures were studied. The capability of dexamethasone to enhance T‐cell proliferation induced by anti‐CD3 with interleukin‐7 in some newborn cord blood mononuclear cell cultures was identified. Dexamethasone suppressed production of interferon‐γ in 68‐h cell cultures stimulated with anti‐CD3 both in the presence of interleukin‐7 and without it. However, a 68‐h cultivation of newborn blood cells with dexamethasone, anti‐CD3 and interleukin‐7 resulted in the accumulation of T‐lymphocytes capable of producing interferon‐γ after restimulation. As a result of it the amount of interferon‐γ producing CD7⁺ T‐cells and the concentration of interferon‐γ in cultural supernatants were maximal in the cell cultures incubated with anti‐CD3, interleukin‐7 and dexamethasone during the first 68 h and subsequently restimulated with phorbol 12‐myristate 13‐acetate and ionomycin. The stimulation of neonatal or adult blood cells by dexamethasone, anti‐CD3 and interleukine‐7 also causes a decrease in the number of naïve T‐cells and central memory cells and an increase in the number of effector memory CD7⁺CD45RA⁺CD62L^– cells in cultures. It is possible that these effects are caused by the influence of dexamethasone on IL‐7 receptor expression: it is known that IL‐7 receptor alpha‐chain gene is a glucocorticoid‐inducible gene.     

Effect of antenatal dexamethasone therapy on maternal plasma human chorionic gonadotrophin, oestradiol and progesterone

The aim of this study was to determine whether the current regimen of dexamethasone administration to induce fetal lung maturation affected the circulating concentrations of placental hormone. A standard regimen of dexamethasone that comprised two doses of 12-mg intramuscular injections, 12 h apart was administered to 12 pregnant women to promote fetal lung maturation in anticipation of premature delivery before 34 completed weeks of gestation. Blood samples were collected before starting the dexamethasone therapy, 24 h, and 48 h after completing therapy for the measurement of the plasma concentrations of human chorionic gonadotrophin (HCG), oestradiol and progesterone. There was a progressive fall in the plasma concentrations of HCG following dexamethasone therapy (P = 0.049 and P = 0.034, 24-h and 48-h post therapy respectively). There was an initial fall in the plasma concentrations of oestradiol after dexamethasone therapy (z = 3.059; P = 0.002, 24-h post therapy), which recovered by 48 h (P = 0.239). There was no difference between the plasma concentrations of progesterone at the three time points. The effect of dexamethasone on HCG concentrations suggests that it has a direct inhibitory effect on placental hormone synthesis or secretion. Further studies are needed to define the mechanism of action of dexamethasone on placental HCG production.     

Inhibition of neutrophil and monocyte recruitment by endogenous and exogenous lipocortin 1

1. The role played by endogenous lipocortin 1 in the anti-migratory action exerted by dexamethasone (Dex) on monocyte recruitment in an in vivo model of acute inflammation was investigated by use of several neutralizing polyclonal antibodies raised against lipocortin 1 or a lipocortin 1-derived N-terminus peptide (peptide Ac2-26). The efficacy of peptide Ac2-26 in inhibiting monocyte and polymorphonuclear leucocyte (PMN) recruitment was also tested.
2. Intraperitoneal (i.p.) injection of zymosan A (1 mg) produced a time-dependent cell accumulation into mouse peritoneal cavities which followed a typical profile of acute inflammation: PMN influx was maximal at 4 h post-zymosan (between 15 and 20×10⁶ cells per mouse), and this was followed by an accumulation of monocytes which peaked at the 24 h time-point (between 10 and 15×10⁶ cells per mouse).
3. Dex administration to mice reduced zymosan-induced 4 h PMN infiltration and 24 h monocyte accumulation with similar efficacy: approximately 50% of inhibition of recruitment of both cell types was achieved at the dose of 30 μg per mouse (∼1 mg kg⁻¹, subcutaneously (s.c.)). Maximal inhibitions of 64% and 67% on PMN and monocyte recruitment, respectively, were measured after a dose of 100 μg per mouse (∼3 mg kg⁻¹, s.c.).
4. Dex (30 μg s.c.) inhibited monocyte (53%) and PMN (69%) accumulation in response to zymosan application in mice which had been treated with a non-immune sheep serum (50 μl s.c.). In contrast, the steroid was no longer active in reducing cell accumulation in mice which had been passively immunized against full length human recombinant lipocortin 1 (serum LCS3), or against lipocortin 1 N-terminus peptide.
5. Treatment of mice with vinblastine (1 mg kg⁻¹, intravenously (i.v.)) produced a remarkable leucopenia as assessed 24 h after administration. This was accompanied by a 60% reduction in 4 h-PMN influx, and by a 27% reduction in 24 h-monocyte accumulation, measured after zymosan administration. The inhibitory effect of Dex on monocyte recruitment was not significantly modified in vinblastine-treated mice, with 36% and 57% of inhibition calculated at the dose of 30 μg Dex, and 70% and 60% of inhibition at 100 μg Dex, in vehicle- and vinblastine-treated mice, respectively.
6. Treatment of mice with peptide Ac2-26 dose-dependently attenuated PMN influx at 4 h post-zymosan with a significant effect at 100 μg per mouse (45% of inhibition, n=9, P<0.05) and a maximal effect of 61% inhibition at the highest dose tested of 200 μg s.c. (n=14, P<0.05). No effect of peptide Ac2-26 (200 μg s.c.) was seen on zymosan-induced 24 h monocyte recruitment. In contrast, administration of 200 μg peptide Ac2-26 every 6 h was effective in reducing the number of monocytes harvested from the inflamed peritoneal cavities at 24 h post-zymosan: 9.40±0.58×10⁶ monocytes per mouse (n=13) and 5.74±0.34 monocytes per mouse (n=14) in vehicle- and peptide Ac2-26-treated mice, respectively (P<0.05).
7. Finally, peptide Ac2-26 produced a concentration-dependent inhibition of the rate of phagocytosis of mouse resident peritoneal macrophages as measured by flow cytometry, with a maximal reduction of 34% at the highest concentration tested of 100 μg ml⁻¹ (n=8 experiments performed in duplicate; P<0.05).
8. In conclusion, this study suggests that in vivo monocyte recruitment during acute inflammation is, at least in part, under the negative modulatory control of endogenous lipocortin 1 (as seen after administration of Dex by using the specific antisera) and exogenous lipocortin 1 mimetics (as observed with peptide Ac2-26). In addition to the neutrophil, we can now propose that the monocyte also can be a target for the in vivo anti-inflammatory action of lipocortin 1.

     

Dexamethasone effects on cerebral protein synthesis prior to and following hypoxia-ischemia in immature rat

We hypothesized that the neuroprotection against cerebral hypoxic-ischemic damage observed with dexamethasone treatment in immature rats is related to a change in cerebral protein synthesis. Six-day-old Wistar rats were injected with either vehicle (10 ml/kg) or dexamethasone (0.1 mg/kg) 24 h prior to cerebral hypoxia-ischemia. Local cerebral protein synthesis (incorporation of 14C-leucine into proteins) was measured in 7-day-old rats during normoxia, during hypoxia-ischemia, and after hypoxia-ischemia which was produced with right carotid artery ligation and 2-h exposure to 8% O2. In normoxic controls, cerebral protein synthesis was similar in dexamethasone and vehicle-treated animals. During hypoxia-ischemia, local cerebral protein synthesis decreased markedly (p < 0.0001) in ischemic regions ipsilateral to the occlusion, irrespective of treatment. After hypoxia-ischemia, protein synthesis declined even further in vehicle-treated animals. Reductions in protein synthesis were substantially more severe in vehicle- than dexamethasone-treated animals, particularly after hypoxia-ischemia (p < 0.0001). Thus, neuroprotection with dexamethasone is not related to a reduction in basal levels of cerebral protein synthesis, but is associated with an improved protein synthesis during and following hypoxia-ischemia.