1. In order to determine whether carbamazepine is an inducer of lymphocyte microsomal epoxide hydrolase, the activity of the enzyme has been measured in the lymphocytes of 40 patients on continuous drug therapy using [3H]-cis stilbene oxide as a substrate. 2. Induction of the cytochrome P450 isoform, CYP3A, has been assessed in the same patients by measurement of the 24 h urinary excretion of 6 beta-hydroxycortisol by radioimmunoassay. The urinary concentrations of carbamazepine and its two metabolites, the 10,11-epoxide and trans-dihydrodiol, have also been measured by h.p.l.c. 3. The 24 h urinary 6 beta-hydroxycortisol excretion in the patients increased with the dose of carbamazepine (r = 0.57, P < 0.001) indicating induction of CYP3A. 4. The total amount of trans-dihydrodiol excreted in the urine increased with the dose of carbamazepine, and it was the most abundant urinary metabolite in all patients and at all dose-levels. There was no relationship between the dose of carbamazepine and the diol to epoxide ratio (r = 0.01, NS). 5. Lymphocyte microsomal epoxide hydrolase activity was marginally, but significantly (P = 0.02) higher in the patients (28.4 pmol diol min-1 mg-1 protein) than in drug-free controls (23.4 pmol diol min-1 mg-1 protein (95% CI for difference -9 to -0.8)). 6. The results indicate that at concentrations of carbamazepine which produce marked induction of hepatic CYP3A, an enzyme involved in the metabolism and bioactivation of carbamazepine, there is only a slight increase in lymphocyte microsomal epoxide hydrolase.

To determine whether elevations of plasma norepinephrine (NE) in major depression represent increased sympathetic nervous system (SNS) activity and to assess the effects of desipramine hydrochloride on sympathetic function.

One hundred and five breast cancer patients with stage T3/4, N+/-, Mo were treated at random either with a pre- and postoperative chemotherapy (A) (5-drug-combination + tamoxifen) or with a pre- and postoperative radiotherapy (B). Paraffin embedded tissue samples were prepared from tumor material taken by biopsy prior to therapy as well as at surgery from patients of both groups to estimate the HER-2 oncogene copy numbers before and after treatment. In 53 and 50% of the pretherapeutic samples the HER-2 gene was amplified in groups A and B, respectively. In the post-therapeutic group 60% of the chemotherapy and 48% of the radiotherapy patients, respectively, had low or high HER-2 oncogene copy numbers. In addition, HER-2 amplification before and after therapy was estimated in 28 patients. An increase of oncogene copy numbers could be detected in 21% of the chemotherapy patients, and a decrease was noted in 11%. No radiotherapy patient showed a rise, but 11% a loss of copy numbers. Although amplification of HER-2 oncogene was not found to be associated with overall survival as it was in many studies before, it could still be a predictor of clinical outcome and the cause of mammary carcinomas developing into stage T3/4.

Population-based pharmacokinetic prediction algorithms have been developed for several medications. A fundamental assumption has been that the kinetics remain constant over time. Carbamazepine (CBZ), however, induces its own metabolism in a concentration- and time-dependent manner. A Bayesian estimation program is presented that models the changing catabolic enzyme activity, linearly related to hepatic microsomal enzyme concentration, along with the serum drug concentration. An Emax model is used for enzyme formation with respect to drug concentration: elimination of enzyme activity is modeled as a first-order process. This program was tested in 22 drug-naive outpatients begun on CBZ monotherapy. The 1 week concentrations were used to prospectively predict concentrations at 1 month of therapy and were very close to actual measurements: prediction bias (mean error of prediction) = -0.1 micrograms/mL and precision (median absolute error of prediction) = 1.2 micrograms/mL. Comparison estimates, made by assuming a constant concentration/dose ratio, had bias = 2.6 micrograms/mL (p < 0.001) and precision = 2.2 micrograms/mL (p = 0.01). We conclude that (1) CBZ autoinduction is not complete after 1 week of therapy and (2) the methodology permits accurate estimation of CBZ pharmacokinetics.

In a prospective, controlled, randomized study where two different agonists were used, we compared three different long desensitization protocols for induction of multiple follicular growth in medically assisted conception cycles. In protocol A, 30 patients were injected with buserelin twice a day for 15 days prior to ovarian stimulation until human chorionic gonadotrophin (HCG) administration. In protocol B, 30 patients were injected with a single dose of long acting Triptorelin (3.75 mg) 15 days before the ovarian stimulation onset. In protocol C, 30 patients were injected with the long acting Triptorelin 4 weeks before ovarian stimulation followed by daily administration of 0.1 mg of the same agonist until HCG injection. There was no difference in the ovarian response to exogenous gonadotrophin stimulation, except for the presence of premature luteinization in two patients in group B. A significantly higher number of mature oocytes was collected from patients with protocol A; however, the fertilization and cleavage rate demonstrated no significant difference among the three groups of patients. The ongoing pregnancy rate and the implantation rate per treatment cycle were very similar in the three study groups. When the convenience, cost and side-effects for the patient are being considered, protocol B should be selected as the first choice when the agonist is utilized for the purpose of inducing pituitary desensitization before and during ovarian stimulation.

To determine the effect of the adjuvant administration of interferon gamma on monocyte HLA-DR antigen expression and mitogen-stimulated interferon gamma production following injury.

beta-Adrenergic receptor responsiveness is impaired in hypertension. A low-sodium diet both corrects this defect and lowers blood pressure. To determine whether upregulation of beta-adrenergic receptor function in hypertension might be related nonspecifically to lowering of blood pressure, vascular beta-adrenergic response was assessed after pharmacologic antihypertensive treatment by use of dorsal hand vein linear differential transformer techniques in patients with hypertension. Subjects were studied after randomized treatments with placebo and verapamil and after randomized treatments with verapamil and hydrochlorothiazide. After 2 weeks of treatment, verapamil lowered blood pressure in the subjects with hypertension but did not significantly upregulate vascular beta-adrenergic response (58% +/- 8% to 68% +/- 8%; p > 0.2 versus placebo). Further vascular beta-adrenergic responsiveness after treatment with hydrochlorothiazide did not significantly differ from that with verapamil (hydrochlorothiazide, 68% +/- 9%; verapamil, 53% +/- 7%; n = 8, p > 0.3). Thus, reduction of blood pressure with either verapamil or hydrochlorothiazide did not correct the defect in beta-adrenergic responsiveness in hypertension. Vascular beta-adrenergic response appears to be regulated selectively in hypertension, not simply by lowering of blood pressure.

One-hundred women undergoing ovarian stimulation with gonadotrophin-releasing hormone agonist (GnRH-a) and a human menopausal gonadotrophin (HMG) for in-vitro fertilization (IVF) participated in this randomized comparative study. The effectiveness of long-acting s.c. goserelin (Zoladex depot; 49 patients) and intranasally (i.n.) administered buserelin acetate (Suprefact; 51 patients) for pituitary down-regulation was compared. Treatment with s.c. goserelin (3.6 mg) or i.n. buserelin acetate (200 micrograms; 6 times/day) was started on day 21-23 of the cycle. Stimulation with 150 IU of HMG/day was started after at least 11 days of GnRH-a treatment. There were no differences in the time required for follicular development nor in the clinical outcome between groups treated with either goserelin or buserelin. The number of oocytes recovered in the goserelin group was 6.7 +/- 5.0 versus 6.3 +/- 4.9 in the buserelin group. There were 11 pregnancies after the use of goserelin (22.4%) and 12 pregnancies in those given buserelin (24.0%). The number of HMG ampoules needed for follicular maturation was higher in the goserelin group (27.9 +/- 7.8) than in the buserelin group (24.6 +/- 7.8, P < 0.05). The patients given buserelin suffered significantly more from tiredness, depression, headache and abdominal pain than those receiving goserelin, whereas there were no differences between the groups in experiencing mental irritability, nausea and swelling. Subcutaneous goserelin depot injection offers a useful alternative for pituitary down-regulation in IVF stimulation.

The hypothalamic-pituitary axis of 22 hyperandrogenic infertile women had suppression with either the gonadotrophin-releasing hormone (GnRH)-analogue buserelin (n = 12) or with an oestrogen-gestagen compound (Diane; n = 12). This was followed by pulsatile GnRH application for inducing ovulation (Zyklomat). In terms of ovulation and pregnancy rates the buserelin pre-treatment was more effective than the steroid pre-treatment, especially in hyperandrogenic non-polycystic ovaries (PCO).

This study investigated the development of functional ovarian cysts during pituitary down-regulation prior to in-vitro fertilization (IVF), and identified 16 cases of cysts in 288 IVF cycles studied. Comparing the patients with functional ovarian cysts to the other 272 IVF cycles, there was no significant difference in age or incidence of endometriosis but significantly (P < 0.01) more patients with cysts had ovulatory dysfunction. The serum progesterone was < 5.7 nmol/l in all 16 patients with cysts on day 4 of the IVF cycle, and in eight of these patients the serum progesterone was < 5.7 nmol/l on the day buserelin was commenced. In 10 of the 16 patients with cysts, serum oestradiol concentrations remained elevated despite the prolonged use of buserelin, and the cysts were aspirated. The aspirate in all cases was clear without any suggestion of endometriosis. The cyst aspirates had significantly lower progesterone (P < 0.001), higher androstenedione (P < 0.01) and similar oestradiol concentrations to 10 follicular fluid samples collected at the time of oocyte retrieval. This study suggests that functional ovarian cysts may develop during pituitary down-regulation, and these cysts are follicular cysts rather than persistent corpora lutea or endometriomata.

Pulmonary dysfunction caused by pulmonary neutrophil sequestration is a frequent postoperative complication in patients undergoing cardiopulmonary bypass (CPB) surgery. It is yet unclear whether treatment with corticosteroids in vivo in these patients can prevent complement-mediated neutrophil activation and sequestration in the lungs. Therefore, we conducted a prospective study in order to investigate whether methylprednisolone (MP) pretreatment (30 mg/kg) could influence the appearance of IL-8 (a recently discovered cytokine with potent neutrophil-chemotactic activity) in the peripheral circulation. We also studied the effects of MP pretreatment on the inflammatory parameters in the bronchoalveolar lavage (BAL) fluid 4 h postoperatively. Although peripheral neutropenia and the rise in IL-8 serum levels was less pronounced in MP-treated than in non-steroid-treated patients, there was no significant difference in albumin, total protein, concentrations of IL-8 and C3a, and the number of neutrophils in the BAL fluid between the two groups. However, when cultured in vitro, alveolar macrophages from patients treated with MP released significantly lower IL-8, both in basal conditions and after stimulation with lipopolysaccharide. Our results show that MP does not prevent (IL-8-mediated) pulmonary neutrophil infiltration after CPB, although it might affect certain aspects of the microvascular lung injury.

Immunoglobulin is known to be an immunomodulator. It can induce protein mediators from mononuclear cells, particularly monocytes in vitro. Intravenous immunoglobulin (IVIg) has been used as a therapy in several clinical situations. In this study, the influence of IVIg infusion on the plasma levels of two protein mediators, interferon-gamma (IFN-gamma) and interleukin-6 (IL-6), was assessed in patients with secondary generalized epilepsy. Compared to preinfusion levels, plasma interferon-gamma was increased in 18 of 18 patients 20 min after the 6- to 8-hr infusion of IVIg. Plasma interferon-gamma levels reached their peak at various times from 20 min to 3 days post IVIg infusion, dependent upon the individual patient. Plasma IL-6 levels also increased after IVIg infusion. Generally, IL-6 reached its peak level after IFN-gamma. No activated T cells or B cells were observed as determined by the expression of surface CD25, CD23, and HLA-DR 20 min following the infusion when the IFN-gamma and IL-6 levels were assessed. The expression of the high-affinity receptor for IgG, CD64, on monocytes was significantly enhanced after IVIg infusion, while the low-affinity receptor for IgG, CD32, was only slightly increased. Cytoplasmic staining of PBMC indicates that both CD16-positive and CD16-negative cells may contribute to the increase seen in plasma IFN-gamma. These data raise the possibility that the therapeutic effects of intravenous immunoglobulin may be related, at least in part, to the immunomodulatory activity as demonstrated by the changes in plasma levels of IFN-gamma and IL-6.

This study was designed to clarify the nature of the reduced function of the peripheral beta adrenoceptor system observed in panic disorder with agoraphobia. The authors hypothesized that this phenomenon reflected a regulatory and adaptive process.

Although corticosteroids are effective in improving asthma symptoms and bronchial responsiveness, their mechanism of action is unknown. We examined whether changes in bronchial responsiveness with corticosteroid therapy of asthma are accompanied by a reduction in cytokine gene expression and eosinophil infiltration in the airways. Bronchoalveolar lavage (BAL) was performed in 18 patients with moderate asthma before and after 2 wk of treatment with prednisolone, 0.6 mg/kg/day, or matched placebo in a randomized double-blind parallel group study. Cells were counted in BAL cytocentrifuge preparations, and the numbers of cells expressing cytokine mRNA were assessed by in situ hybridization using 35S-labeled RNA probes. When the actively treated and placebo groups were compared, there was a decrease in airway methacholine responsiveness (p < 0.01) after prednisolone. This was accompanied by a decrease in bronchoalveolar lavage eosinophils (p < 0.05), a reduction in the numbers of BAL cells per 1,000 expressing mRNA for interleukin-4 (IL-4, p < 0.01) and interleukin-5 (IL-5, p < 0.005), and an increase in numbers of cells expressing mRNA for interferon-gamma (p < 0.005). These results are compatible with the hypothesis that the beneficial effects of corticosteroids in asthma may result from modulation of cytokine production, with consequent inhibition of local bronchial eosinophilia.

1. A double-blind placebo-controlled study was conducted on the effects of oral terbutaline (beta 2-adrenoceptor agonist) and propranolol (beta 1 beta 2-adrenoceptor antagonist) on basal heat production of skeletal muscle, measured ex vivo by direct microcalorimetry. Terbutaline slow-release 7.5 mg, propranolol 80 mg, and matching placebo were randomly administered twice daily for 1 week to 15 healthy males, using a cross-over design. 2. Resting heat production in biopsied vastus lateralis was lowered by median 27% (P < 0.01) after terbutaline medication as compared with placebo. The cause of this hypometabolism at the cellular level is obscure but may possibly be explained by desensitization of beta 2-receptors. 3. Propranolol decreased the metabolic rate by 17% (P > 0.3); this might imply that the sympathetic nervous system is playing only a minor role in the regulation of basal metabolic rate in muscle, or that up-regulation of beta-receptors had influenced the decline. 4. The muscle utilized about 6% of its total energy for the Na-K pump as assessed after inhibition by ouabain. 5. Serum potassium was significantly lowered by terbutaline and slightly increased by propranolol with no relationship between changes in extracellular levels and muscle content of potassium under resting conditions. Energy values for the Na-K pump in muscle after 1 week of terbutaline or propranolol medication were similar to placebo. The results are not consistent with the hypothesis that decreased serum potassium during continuous beta 2-adrenoceptor agonist treatment is due to a chronically activated Na-K pump, at least not in resting muscle.

alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. Levels of ODC are closely related to tumor promotion, and inhibition of ODC is associated with suppression of tumor development in laboratory animals. DFMO has shown a dose-response effect in tumor inhibition in mice.

The purpose of this study was to test the hypothesis that there is homologous upregulation of arterial alpha-adrenergic responsiveness during suppression of sympathetic nervous system (SNS) activity in humans. 10 subjects (19-28 yr) were studied during placebo and when SNS activity was suppressed by guanadrel. Changes in forearm blood flow (FABF) mediated by the intraarterial infusion of norepinephrine (NE), angiotensin II (AII), and phentolamine were measured by plethysmography. During guanadrel compared with placebo, plasma NE levels (1.28 +/- 0.09-0.85 +/- 0.06 nM; P = 0.0001) and the extra vascular NE release rate derived from [3H]NE kinetics were lower (7.1 +/- 0.7-4.0 +/- 0.2 nmol/min per m2; P = 0.0004), suggesting suppression of SNS activity. During guanadrel, there was increased sensitivity in the FABF response to NE (analysis of variance P = 0.03). In contrast, there was no difference in the FABF response to AII (analysis of variance P = 0.81), suggesting that the upregulation observed to NE was homologous. The increase in FABF during phentolamine was similar during guanadrel compared with placebo (guanadrel: 141 +/- 37 vs. placebo; 187 +/- 27% increase; P = 0.33), suggesting that there was at least partial compensation to maintain constant endogenous arterial alpha-adrenergic tone. We conclude that there is homologous upregulation of arterial alpha-adrenergic responsiveness in humans when SNS activity is suppressed by guanadrel.

Platelet-derived growth factor (PDGF) is a potent mitogen thought to propagate atherosclerosis and other proliferative or inflammatory diseases. Some of these diseases are ameliorated in humans by ingestion of omega-3 fatty acids. We investigated mRNA expression of both PDGF-A and PDGF-B in quiescent peripheral blood mononuclear cells from healthy male volunteers. For this, a highly sensitive, quantitative polymerase chain reaction strategy (3n-PCR) was developed. In contrast to granulocytes, both PDGF-A and PDGF-B mRNAs are expressed in mononuclear cells. This expression occurs at a remarkably constant rate. Moreover, effects of 7 g/d of a 85% omega-3 fatty acid fish oil concentrate were investigated in a 6-week controlled, randomized, observer-blind study in 14 human volunteers, 7 of whom served as controls. omega-3 Fatty acids increased in mononuclear cell phospholipids. We demonstrate for the first time that diet affects human gene regulation. Dietary omega-3 fatty acids downregulate gene expression of both PDGF-A (-66%), and PDGF-B (-70%). This may represent a novel mechanism for the antifibrotic and antiatherosclerotic action of omega-3 fatty acids.