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Biomedical subjects

A M Freeman

Publications and source records attributed to A M Freeman.

At least 19 recordsLinked to original sources
PubMed2001

Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine.

Treatment of schizophrenics with some antipsychotic drugs has been associated with an increased incidence of hyperglycemia and new-onset type 2 diabetes. Some of these drugs also inhibit glucose transport in rat pheochromocytoma (PC12) cells. The current study was designed to examine the effects of the atypical antipsychotic drugs--risperidone, clozapine and analogs of clozapine on glucose uptake in PC12 cells. Glucose transport was measured in cells incubated with vehicle or drug over a range of concentrations (0.2-100 microM). Uptake of 3H-2-deoxyglucose was measured over 5 min and the data were normalized on the basis of total cell protein. Risperidone and clozapine inhibited glucose transport in a dose-dependent fashion with IC(50)'s estimated to be 35 and 20 microM, respectively. The clozapine metabolite, desmethylclozapine, was considerably more potent than the parent drug, whereas clozapine N-oxide was essentially inactive. The structural analogs of clozapine, loxapine and amoxapine, both inhibited glucose transport with amoxapine being the least potent. The ability of the drugs to inhibit glucose transport was significantly decreased by including 2-deoxyglucose (5 mM) in the uptake medium. Schild analysis of the glucose sensitivity of clozapine, loxapine and risperidone indicated that 2-deoxyglucose non-competitively antagonized the inhibitory effects of these drugs. Moreover, clozapine and fluphenazine inhibited glucose transport in the rat muscle cell line, L6. These studies suggest that the drugs may block glucose accumulation directly at the level of the glucose transporter (GLUT) protein in cells derived from both peripheral and brain tissue. Furthermore, this work may provide clues about how the antipsychotic drugs produce hyperglycemia in vivo.

Animals↗
PubMed2001

Glucose metabolism in relation to schizophrenia and antipsychotic drug treatment.

It has been reported in the earlier literature that many patients with psychoses had abnormalities in glucose metabolism as revealed by glucose tolerance testing. This observation is reinforced by the fact that the schizophrenic population appears to have about a 2-3-fold increased risk for Type II diabetes mellitus. However, some uncertainty remains about the relative risk value because there have been numerous case reports of patients who developed hyperglycemia and even Type II diabetes apparently as a consequence of treatment with antipsychotic drugs. Schizophrenic patients with abnormal glucose metabolism have a higher prevalence of drug-induced tardive dyskinesia than patients with a normal glucose profile. Treatment with the new atypical antipsychotics has a much lower risk of movement disorders; however, weight gain, hyperglycemia, and diabetes are emerging as significant side effects. Because glucose is essential for energy metabolism in neurons, any change in the effective glucose levels in brain that result from drug therapy may have significant clinical implications. It is not clear whether the glycemic state of schizophrenics contributes to their psychotic symptoms or modulates the incidence of drug side effects. Basic research shows that the drugs which cause hyperglycemia in patients appear to inhibit neuronal glucose transport which may partly explain their effects. This paper reviews the relevant literature in a preliminary attempt to understand the implications of such clinical findings in the light of basic research.

Antipsychotic Agents↗
PubMed2000

Prodromal schizophrenia and atypical antipsychotic treatment.

Early recognition and intervention in psychosis is the focus of more intensive research. In this paper, we critically review the ideas that have emerged in this field. We also propose a model or hypothesis for testing in the prodromal phase of schizophrenia. Attention to practical and ethical issues, particularly with the use of atypical antipsychotics in one arm of the protocol, is addressed. Studies by Yung and Falloon describe prodromal intervention with psychosocial strategies and time-limited low potency neuroleptics, respectively, that suggest benefits of such a model. Although we have respect for the DSM system, this paper is written more from a Bleulerian than Kraepelinian perspective in that we emphasize affective, cognitive, and negative symptoms in addition to positive symptoms. The paper recognizes the strong conceptual disagreements implicit in this area stemming not only from Kraepelin and Bleuler but work from the 1930s by Cameron. The clinical research advocated is timely in that the atypicals are more congruent to the Bleulerian conception with a neurodevelopmental hypothesis of schizophrenia. We also have exciting new imaging and genetic technologies to refine our concepts of schizophrenia and its prodromal and premorbid phases.

Age of Onset↗
PubMed2000

Prostaglandin G/H synthase-2 is required for maximal formation of osteoclast-like cells in culture.

We examined the effect on osteoclast formation of disrupting the prostaglandin G/H synthase genes PGHS-1 and-2. Prostaglandin E(2) (PGE(2)) production was significantly reduced in marrow cultures from mice lacking PGHS-2 (PGHS-2(-/-)) compared with wild-type (PGHS-2(+/+)) cultures. Osteoclast formation, whether stimulated by 1,25-dihydroxyvitamin D(3) (1,25-D) or by parathyroid hormone (PTH), was reduced by 60-70% in PGHS-2(-/-) cultures relative to wild-type cultures, an effect that could be reversed by providing exogenous PGE(2). Cultures from heterozygous mice showed an intermediate response. PGHS inhibitors caused a similar drop in osteoclast formation in wild-type cultures. Co-culture experiments showed that supporting osteoblasts, rather than osteoclast precursors, accounted for the blunted response to 1,25-D and PTH. This lack of response appeared to result from reduced expression of RANK ligand (RANKL) in osteoblasts. We cultured spleen cells with exogenous RANKL and found that osteoclast formation was 50% lower in PGHS-2(-/-) than in wild-type cultures, apparently because the former cells expressed high levels of GM-CSF. Injection of PTH above the calvaria caused hypercalcemia in wild-type but not PGHS-2(-/-) mice. Histological examination of bone from 5-week-old PGHS-2(-/-) mice revealed no abnormalities. Mice lacking PGHS-1 were similar to wild-type mice in all of these parameters. These data suggest that PGHS-2 is not necessary for wild-type bone development but plays a critical role in bone resorption stimulated by 1,25-D and PTH.

Animals↗
PubMed1999

Millon multiaxial personality patterns differentiate depressed and anxious outpatients.

Ninety-three patients, including 47 patients with Generalized Anxiety Disorder (GAD) and 46 patients with Major Depression (MD), were entered into recent clinical trials. Clinicians acknowledge that during the initial screening process, clear separation between depressed and anxious patients may be difficult. By using the DSM-IV criteria, the Hamilton Depression and Anxiety Scales, and a variety of other structured evaluations, patients were divided into the two diagnostic groups. The Millon Multiaxial Inventory (MCMI-III) was administered to all 93 patients as part of their initial assessment, but was not used in the diagnostic decision making process or in assignment to a particular clinical study. Upon completion of these studies, the Millon data were analyzed utilizing a cutoff score of 75, conforming to previous studies. Statistically significant differences in Millon personality patterns between MD and GAD patients included dependent, obsessive-compulsive, self-defeating, and borderline traits. Patients exhibiting dependent, self-defeating, and borderline patterns were statistically more likely to be included in clinical trials of MD rather than GAD. Also, patients with MD were more likely to disclose clinical information and exhibit self-critical behavior when compared to those with GAD. These results suggest that the MCMI-III may detect personality differences between anxious and depressed outpatients presenting for clinical trials.

Adult↗
PubMed1994

Soluble recombinant complement receptor 1 inhibits inflammation and demyelination in antibody-mediated demyelinating experimental allergic encephalomyelitis.

Activation of complement may contribute to tissue damage in many inflammatory diseases, including those that are clearly T cell driven. We have previously provided evidence that C is involved in tissue damage in multiple sclerosis and in the animal models of this disease, experimental allergic encephalomyelitis and Ab-mediated demyelinating experimental allergic encephalomyelitis, the latter being a model more closely resembling multiple sclerosis. The development of a soluble recombinant form of human complement receptor 1 (sCR1) with potent C-inhibiting activity both in vitro and in vivo provides a potential means of preventing C-mediated tissue damage in animal models and in human disease. Here, we describe the effects of this agent on clinical disease and pathology in Ab-mediated demyelinating experimental allergic encephalomyelitis in the rat. Daily i.p. injection of sCR1 (20 mg/kg) over 6 days completely suppressed serum C activity, reduced the severity of clinical disease (clinical score 1.33 vs 2.79 in untreated animals), inhibited central nervous system inflammation (inflammatory index 2.76 vs 6.55), and almost completely blocked demyelination (average 2.43% cord cross-section vs 8.81%). Deposition of C components C1, C3, and C9 was also markedly inhibited in sCR1-treated animals. This dramatic effect on a demyelinating disease, achieved using a well-tolerated biologic reagent, offers an exciting new prospect for therapy in multiple sclerosis.

Animals↗
PubMed1994

Pharmacological properties of a novel ACAT inhibitor (CP-113,818) in cholesterol-fed rats, hamsters, rabbits, and monkeys.

The novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor CP-113,818 has been characterized in vitro against ACAT isolated from liver and intestine from a variety of species including human subjects, and in vivo in cholesterol-fed rats, hamsters, rabbits, and two species of nonhuman primates. CP-113,818 is a potent and specific inhibitor of liver and intestinal ACAT with IC50s ranging from 17 to 75 nM. This ACAT inhibitor also prevented the absorption of exogenous radiolabeled cholesterol in hamsters (ED50 = 6 micrograms/kg), rabbits (ED50 1/2 10 micrograms/kg), and cynomolgus and African green monkeys (40 and 26% inhibition at 10 mg/kg, respectively). CP-113,818 effectively prevented the increase in liver cholesterol levels in cholesterol-fed rats, hamsters, and rabbits. In lipoprotein characterization studies in rabbits, CP-113,818 selectively decreased apoB-containing lipoproteins (beta-VLDL, IDL, and LDL) and shifted the distribution of cholesterol from beta-VLDL, IDL, and LDL (96% before treatment to 81% after treatment) to HDL (4% before treatment to 19% after treatment). Finally, in monkeys, CP-113,818 significantly decreased LDL cholesterol by approximately 30% while either increasing HDL cholesterol (cynomolgus monkeys) or not affecting HDL cholesterol (African green monkeys), thereby improving the total plasma cholesterol/HDL ratios. In summary, CP-113,818 significantly inhibited cholesterol absorption, prevented the increase in liver cholesterol, and improved the lipoprotein profiles by selectively decreasing the cholesterol concentrations of the atherogenic lipoproteins (VLDL, IDL, and LDL) in a variety of cholesterol-fed animals. These data suggest that ACAT inhibition may be a useful therapeutic approach for lowering LDL cholesterol and thereby reducing the risk of developing coronary heart disease.

Animals↗
PubMed1993

The interaction of soluble human complement receptor type 1 (sCR1, BRL55730) with human complement component C4.

Human CR1 is a membrane-bound protein which plays an important role in the control of the human complement system. In addition to its involvement in the processing and clearance of immune complexes with C3b or C4b on their surface, CR1 acts as a cofactor for the proteolysis of C3b and C4b by Factor I. sCR1 is a recombinant, soluble form of CR1 which retains the cofactor activities of CR1, and is of potential therapeutic value for the suppression of complement-mediated tissue damage in vivo. An assay has been established using microtitre plates to explore the binding of sCR1 to the two isotypes of C4, C4A and C4B, and to C4 fragments. Specific binding of 125I-sCR1 to C4b and ammonia-treated C4 has been demonstrated. The binding of 125I-sCR1 to ammonia-treated C4 is dependent on pH and ionic strength, decreasing with an increase in pH and with an increase in ionic strength. At physiological ionic strength, up to twice as much 125I-sCR1 bound to ammonia-treated C4A as bound to ammonia-treated C4B. This preference of sCR1 for binding to the C4A isotype has implications for the clinical association of immune complex disease with C4A null alleles.

Ammonia↗
PubMed1992

A double blind, multicentre, placebo controlled trial of lornoxicam in patients with osteoarthritis of the hip and knee.

Lornoxicam is a new non-steroidal anti-inflammatory agent (NSAID) with a similar pharmacological profile to other oxicams and a potency 10 times greater than piroxicam. A multicentre, randomised, double blind, parallel group study was undertaken to compare the efficacy and tolerance of four weeks' treatment with lornoxicam (6 mg once daily, 4 mg twice daily, and 6 mg twice daily) and placebo in patients with osteoarthritis of the hip or knee. A dose related efficacy of lornoxicam was shown by the numbers of patients in each treatment group who withdrew from the trial owing to inadequate symptom relief (12/40 (30%) receiving placebo, 6/40 (15) receiving lornoxicam 6 mg daily, 4/40 (10%) receiving lornoxicam 8 mg daily, and none receiving lornoxicam 12 mg daily). This effect was confirmed by pain relief scores, which were significantly better than placebo during treatment with lornoxicam 8 mg and 12 mg daily, the effect of 12 mg daily being significantly superior to that of 8 mg daily. Similar results were obtained from functional status scores. Mean functional index (Lequesne) scores were significantly greater than placebo only at a daily dose of 12 mg lornoxicam. Lornoxicam was generally well tolerated, though some gastrointestinal side effects were seen as has been reported with other NSAIDs. Laboratory investigations showed no evidence of drug toxicity.

Administration, Oral↗
PubMed1989

A large multicentre, parallel group, double-blind study comparing tenoxicam and piroxicam in the treatment of osteoarthritis and rheumatoid arthritis.

A total of 1,328 patients with osteoarthritis or rheumatoid arthritis were entered into this double-blind, parallel group study of tenoxicam and piroxicam. The patient populations were well matched. An improvement was seen in pain on moving and at night in both groups and in both indications. Stiffness was also improved by both drugs, being most marked in the rheumatoid arthritis group. The primary efficacy variable was global assessment, and this showed tenoxicam to have slightly greater effect in osteoarthritis and the reverse in rheumatoid arthritis. There were no statistically significant differences in any of these findings. There were no significant differences in tolerance ratings, although the more serious gastrointestinal events occurred in the piroxicam group.

Adult↗
PubMed1988

Psychopathology of chronic haemodialysis: is it a behavioural cognitive continuum?

Neuropsychiatric complications of chronic renal haemodialysis cover a wide gamut of clinical syndromes. These pictures can be diagnostically classified as non-psychotic and psychotic-like syndromes. On the basis of a review of the literature, some nosological precisions are formulated, and a hypothesized cognitive-behavioural psychopathological continuum is presented. The hypothesis postulates that a central cognitive disturbance, due to multiple organic aetiopathogenic factors, results in a step-wise decline, initially disguised as an affective, neurotic or personality disorder, and further deteriorating into the well-known "dialysis dementia", with a variety of other clinical presentations in between. Additional research in the biological and psychosocial areas is needed to verify different aspects of these conditions, their validity in the context of the authors' hypothesis, and their relevance to the overall "quality of life" of chronic haemodialysis patients.

Cognition Disorders↗
PubMed1988

Cognitive dysfunction after coronary artery bypass surgery: a case-controlled study.

Twenty-two patients screened from a sample of 391 having coronary artery bypass grafting (CABG) showed significant declines on the Mini-Mental State Examination (MMSE) administered preoperatively and four days postoperatively. The MMSE is a 30-point cognitive function screening instrument for dementia and delirium. These patients were compared with 22 matched control subjects who exhibited intact cognitive function postoperatively. The study assessed the association between postoperative cognitive dysfunction and socioeconomic status, potential effects of selected surgical/anesthetic factors, and preoperative anxiety and depression (Zung Anxiety and Center for Epidemiologic Studies-Depression [CES-D] self-rating scales). The results indicate that a higher preoperative level of depression reported on the CES-D (mean score of study patients 22.1 versus 12.7 for controls) is significantly associated with the development of postoperative cognitive dysfunction (P less than .01). The educational and occupational levels of study patients were significantly below those of controls (P less than .01, P less than .02). Occurrence of a postoperative complication was the only surgical/anesthetic factor found to be significantly associated with cognitive dysfunction (P less than .01). These findings suggest that preoperative depression significantly increases the risk for immediate postoperative cognitive dysfunction, and that lower socioeconomic status may confer greater risk for postoperative cognitive morbidity.

Adult↗
PubMed1988

Denial: predictor of outcome following coronary bypass surgery.

Using a modified version of the Hackett-Cassem denial scale we measured preoperative denial in 121 patients scheduled for CABG surgery. A significant inverse relationship was found between the denial scale and Hamilton Anxiety measures four days postoperatively (p less than .02). Longitudinal assessments were carried out using the Spielberger State Anxiety Inventory (SSAI), the Zung Self-Rating Depression Scale (Zung SDS) and the Psychosocial Adjustment to Illness Scale (PAIS). Six months following the surgery, significant negative relationships between denial and these self-report outcome measures were observed as follows: denial and SSAI (p less than .001), denial and Zung SDS (p less than .01), and denial and PAIS (p less than .01). However, the same analysis at twelve months showed no statistically significant correlations between denial and these psychologic outcome measures. Our findings suggest that denial serves as an adaptive mechanism, especially in the immediate postoperative period. Furthermore, higher levels of denial may be predictive of improved psychologic outcome for up to six months following surgery. Subsequently, however, other events, unrelated to the surgery, may be of greater importance than preoperative denial in determining psychological outcome from CABG surgery.

Anxiety Disorders↗