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Biomedical subjects

E A Mueller

Publications and source records attributed to E A Mueller.

88 records · Page 5Linked to original sources
PubMed1985

Neuroendocrine effects of M-chlorophenylpiperazine, a serotonin agonist, in humans.

M-Chlorophenylpiperazine (m-CPP) produces effects on the central serotonergic system in animals compatible with direct agonist activity on postsynaptic serotonin receptors. Although it is a metabolite of the antidepressant trazodone, m-CPP has not previously been given to humans. To evaluate the neuroendocrine, behavioral, and physiological effects of m-CPP, 15 normal subjects were given 0.5 mg/kg m-CPP, orally. Administered acutely under double blind, placebo-controlled conditions, m-CPP was well tolerated by 14 of the 15 subjects; it produced significant increases in plasma PRL and cortisol and in body temperature, without changing pulse or blood pressure. The mean (SD) maximal increases over baseline for PRL, cortisol and temperature were 13.4 (9.9) ng/ml, 10.1 (6.7) micrograms/100 ml, and 0.4 (0.2) C, respectively. A small but significant increase in self-rated activation-euphoria and anxiety was noted by some subjects, whereas there were no significant effects on ratings of depression, dysphoria, altered self-reality, or functional impairment. These results are similar to those for other serotonin agonists and, thus, suggest that m-CPP merits further study as a pharmacological probe of serotonergic responsivity in humans. The results also support the hypothesis that serotonin plays a role in the regulation of PRL, cortisol, body temperature, and mood.

Adult↗
PubMed1984

Neuroendocrine and behavioral effects of m-chlorophenylpiperazine administration in rhesus monkeys.

The effects of m-chlorophenylpiperazine (mCPP), a serotonin receptor agonist, on the release of plasma prolactin (PRL), growth hormone (GH), and cortisol in the rhesus monkey were studied. mCPP was administered intravenously at doses of 0.5, 1.5, and 3.0 mg/kg. GH and cortisol were increased significantly at all doses while PRL was significantly increased only following administration of 3.0 mg/kg mCPP. mCPP administration also produced behavioral alterations in each monkey, including sedation, penile erection, and defecation. PRL, GH and behavioral responses to mCPP were completely blocked by pretreatment with the serotonin antagonist metergoline (MTG). However, pretreatment treatment with MTG failed to entirely anagonize the cortisol response to mCPP. These data suggest that mCPP has prominent neuroendocrine and behavioral effects which are mediated, in part, by serotonergic mechanisms.

Animals↗
PubMed1984

Biological markers in obsessive-compulsive and affective disorders.

To explore the relationship between obsessive-compulsive disorder (OCD) and affective disorder, patients with OCD were studied using a series of biological markers which have been previously reported to be abnormal in patients with affective illness. These "markers" included the dexamethasone suppression test, sleep electroencephalography, the plasma growth hormone response to clonidine, and platelet 3H-imipramine binding. Results from each of these studies suggested similarities between patients with obsessional disorder and those with affective illness. Many of these biological abnormalities were evident in obsessional patients who did not manifest depressive symptoms. As a tricyclic antidepressant, clomipramine, has been found to reduce obsessional symptoms, the relationship between these "affective-like" laboratory findings and the clinical response to clomipramine was studied in a subgroup of OCD patients. Preliminary results suggest that none of the markers studied predict clomipramine response.

Blood Platelets↗
PubMed1984

High dose naloxone in depression.

The behavioral effects of a 2 mg/kg iv bolus infusion of naloxone were compared with a placebo infusion using a double-blind design in a small group of inpatient depressives (n = 6) and normals (n = 8). Naloxone produced consistent and significant worsening in the rated signs and subjective symptoms of depression in the patients. In the normals, lesser changes in Hamilton depression and BPRS total scores were observed while none of the subjective scales were significantly altered. The data suggest that depressives manifest a more marked and subjectively more intense response to naloxone compared to normals. Further studies are required to confirm this preliminary finding and to clarify its relationship to the pathogenesis of depression.

Adult↗
PubMedDate not supplied

Biochemical characterization of a component in extracts of Viscum album enhancing human NK cytotoxicity.

Enhancement of human NK cytotoxicity in the presence of fresh Viscum album extract and some commercial V. album extracts Iscador correlated strictly with an increased formation of lytic effector cell/K562 tumor cell conjugates in the single-cell assay. Both activities were completely destroyed by pretreatment of V. album extracts with pectinase, hemicellulase, amyloglucosidase and alpha-glucosidase, but not with proteases and RNase, i.e., the activities are linked to a polysaccharide. The active component in V. album extract was non-dialysable at a molecular weight cutoff of 10,000. Inhibition of both activities was observed with D-galacturonic acid, poly-galacturonic acid and pectins. The site of galacturonic acid-specific interaction could be identified on the effector cells. The rate of effector cell/tumor cell conjugate formation in the presence of V. album extracts, as well as the abrogation of both activities by pretreatment of V. album extracts with exoglycosidases specific for sugars other than galacturonic acid indicated an action of the NK cytotoxicity-enhancing component on the basis of a bridging mechanism. However, no conclusive results could be obtained for the structural specificity of the site interacting with the target cells.

Binding Sites↗
PubMedDate not supplied

Chemical specificity of effector cell/tumor cell bridging by a Viscum album rhamnogalacturonan enhancing cytotoxicity of human NK cells.

The component in Viscum album extract Iscador-M enhancing the NK cytotoxicity of human CD56+CD3- NK cells (87-95% enrichment) in cocultures with K562 tumor cells and increasing the formation of NK cell/tumor cell conjugates was identified as a rhamnogalacturonan. Both activities were abolished by treatment of V. album extract with poly-alpha-D-galacturonidase and alpha-rhamnosidase and both activities were inhibited in the presence of galacturonic acid and acetylated rhamnose (6-deoxymannose). Inhibition was also observed in the presence of structurally related derivatives such as acetylated mannose or acetylated mannonic acid gamma-lactone, the latter exhibiting a 5-10-fold higher inhibitory potential. The rapid formation of NK cell/tumor cell conjugates in the presence of V. album extract was based on the bridging of NK cells with tumor cells by rhamnogalacturonan. Using a specifically adapted agglutination assay, the saccharide residues of the rhamnogalacturonan interacting with NK cells and tumor cells could be identified by the formation of homologous cell conjugates induced by acetylated rhamnose or acetylated mannose conjugated to dextran and by polygalacturonic acid: terminal acetylated rhamnose or acetylated mannose bound only to NK cells in a dose-dependent manner but not to K562 tumor cells, and terminal galacturonic acid only to K562 tumor cells but not to NK cells. This type of bridging represents a novel mechanism of enhancement of NK cytotoxicity.

Agglutination Tests↗
PubMedDate not supplied

A randomized, double-blind study on the efficacy and safety of a practical three-day regimen with artesunate and mefloquine for the treatment of uncomplicated Plasmodium falciparum malaria in Africa.

A randomized, double-blind, parallel-group study in 104 hospitalized patients with acute, uncomplicated Plasmodium falciparum malaria was performed in West and Central Africa from March to July 2001. Patients were randomized to receive simultaneous dosing (artesunate 200 mg/d plus mefloquine 250 mg/d from the first to the third day [investigational group]) or sequential dosing (artesunate 200 mg/d for 3 d plus mefloquine 250 mg on the second and 500 mg on the third day [reference group]). Patients were followed-up for 28 d, and clinical and parasitological outcomes were assessed. The 14-d cure rate was 100% in the investigational group and 98% in the reference group with no recrudescence until day 28. Mean times to fever and parasite clearance were similar between the 2 groups (32 h vs. 26 h and 45 h vs. 48 h) and tolerability was good in both groups. The number of patients with vomiting was statistically significantly lower in the investigational group compared to the reference group (3.8% vs. 19.2%, P = 0.014). A 3-d once-daily co-administration of artesunate and mefloquine starting on day one offers a practical dosing regimen, which is highly effective and well tolerated in patients with uncomplicated P. falciparum malaria.

Adolescent↗
PubMedDate not supplied

Bioequivalence of soft gelatin capsules and oral solution of a new cyclosporine formulation.

STUDY OBJECTIVE: To compare the bioavailability of cyclosporine from two oral dosage forms of a new microemulsion formulation. DESIGN: Open, randomized, three-treatment, three-period crossover investigation. SETTING: University-affiliated clinical pharmacology research unit. PATIENTS: Twenty-four healthy male volunteers. INTERVENTIONS: Single oral administrations of cyclosporine 180 mg given as a soft gelatin capsule (reference), an oral solution under fasting conditions, and the oral solution mixed with orange juice. MEASUREMENTS AND MAIN RESULTS: Serial venous blood samples were obtained over 48 hours after each administration to measure cyclosporine in whole blood by a specific monoclonal radioimmunoassay. For all three treatments, the mean maximum blood concentration (Cmax) of approximately 1100 ng/ml was reached at about 1.3 hours (tmax) after administration; the area under the blood concentration-time curve (AUC) was, on average, 4700 ng.hr/ml. Bioequivalence was conclusively demonstrated for both the absorption rate (Cmax and tmax) and extent (AUC) of cyclosporine among the treatments inasmuch as the point estimates and 90% confidence intervals were within the respective equivalence ranges. CONCLUSIONS: When administered in conjunction with routine concentration monitoring, the two oral dosage forms of the new microemulsion formulation of cyclosporine can be interchanged without need for dosage adjustments. In addition, the oral solution can be mixed with fruit juice without affecting the rate or extent of cyclosporine absorption.

Administration, Oral↗
PubMedDate not supplied

Pharmacokinetics of dexamethasone and valspodar, a P-glycoprotein (mdr1) modulator: implications for coadministration.

STUDY OBJECTIVE: To assess the potential for a drug-drug interaction between valspodar, a P-glycoprotein (mdrl) modulator used as a chemotherapy adjunct, and dexamethasone, widely included in oncology antiemetic regimens. DESIGN: Randomized, open-label, three-period crossover study. SETTING: Clinical pharmacology research center. SUBJECTS: Eighteen healthy men volunteers (age 25.8+/-3.5 yrs, weight 71.6+/-10.3 kg). INTERVENTIONS: Subjects received single fasting oral doses of valspodar 400 mg, dexamethasone 8 mg, and both drugs concomitantly with 2- to 3-week washout phases between administrations. MEASUREMENTS AND MAIN RESULTS: Lack of a pharmacokinetic drug-drug interaction with respect to valspodar was conclusively demonstrated for both Cmax,b (2.3+/-0.4 vs 2.4+/-0.5 microg/ml) and AUCb (19.8+/-4.8 vs 19.6+/-4.9 microg x hr/ml) inasmuch as bioequivalence criteria were satisfied when comparing administration alone with coadministration, respectively. Although no changes in the rate of dexamethasone absorption were noted on coadministration with valspodar (Cmax 88+/-23 vs 91+/-20 ng/ml), overall exposure was significantly increased by 24% on average (AUC 400+/-87 vs 494+/-90 ng x hr/ml). Regression analysis of valspodar Cmax,b and AUCb during coadministration versus the extent of the interaction (percentage increase in dexamethasone AUC) did not reveal a concentration-effect relationship (p=0.7299 and 0.9718, respectively). CONCLUSION: Given dexamethasone's wide therapeutic index and the short duration of coadministration foreseen for these drugs in a clinical setting (maximum 1 wk/chemotherapy cycle), the 24% increase in dexamethasone's AUC is unlikely to be relevant. Thus no alterations in valspodar or dexamethasone dosages appear warranted when the two drugs are coadministered. Multiple-dose experience in patients would be desirable to confirm these conclusions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗