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S J Donovan

Publications and source records attributed to S J Donovan.

14 recordsLinked to original sources
PubMed2002

An in-vitro evaluation of lectin cytotoxicity using cell lines derived from the ocular surface.

Lectins are proteins or glycoproteins of non-immune origin capable of binding to one or more specific sugar residues. The potential for using lectins as a means of locating and "anchoring" a drug delivery system to a target site on a mucosal surface in order to promote controlled drug delivery and enhanced absorption has been described in previous work. Toxicity is evident for many lectins, and this study has investigated the cytotoxicity of lectins to cells derived from the cornea and conjunctiva. Cultures of transformed cell lines from the conjunctiva and cornea were exposed to solution of lectins, and the viability of these cells assessed by their ability to take up an MTT stain relative to the control. Clear evidence of lectin cytotoxicity was apparent for all of the lectins tested in this study, particularly at higher concentrations and over the longer (48 h) time period. This would raise issues with their potential use in targeted drug delivery systems. The lectins from Lycopersicon esculentum and Helix pomatia appeared to show the least cytotoxic activity and so could be considered the most promising. The lectins from Solanum tuberosum and Triticum vulgaris showed significant cytotoxicity, which contrasts with previous in-vivo studies. However, they might be considered for investigation as targeted therapeutic agents in the treatment of malignant diseases.

Antineoplastic Agents↗
PubMed2001

Regulation of glucocorticoid receptor alpha and beta isoforms and type I 11beta-hydroxysteroid dehydrogenase expression in human skeletal muscle cells: a key role in the pathogenesis of insulin resistance?

Glucocorticoid excess frequently results in obesity, insulin resistance, glucose intolerance, and hypertension and may be the product of altered glucocorticoid hormone action. Tissue sensitivity to glucocorticoid is regulated by the expression of glucocorticoid receptor isoforms (GRalpha and GRbeta) and 11beta-hydroxysteroid dehydrogenase type I (11betaHSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed the expression of GRalpha, GRbeta, and 11betaHSD1 and their hormonal regulation in skeletal myoblasts from men (n = 14) with contrasting levels of adiposity and insulin resistance. Immunohistochemical, Northern blot, and Western blot analysis indicated abundant expression of GRalpha and 11betaHSD1 under basal conditions. The apparent K(m) and maximum velocity for the conversion of cortisone to cortisol were 440 +/- 14 nmol/L and 75 +/- 7 pmol/mg protein.h and 437 +/- 16 nmol/L and 33 +/- 6 pmol/mg protein.h (mean +/- SEM; n = 4) in the presence and absence of 20% serum. Incubation of myoblasts with increasing concentrations of glucocorticoid (50-1000 nmol/L) resulted in a dose-dependent decline in GRalpha expression and a dose-dependent increase in GRbeta expression. 11betaHSD1 activity was sensitively up-regulated by increasing concentrations of glucocorticoid (50-1000 nmol/L: P < 0.05). Abolition of these effects by the GR antagonist, RU38486, indicates that regulation of GRalpha, GRbeta, and 11betaHSD1 expression is mediated exclusively by the GRalpha ligand-binding variant. In contrast, 11betaHSD1 was down-regulated by insulin (20-100 mU/mL: P < 0.01) in the presence of 20% serum, whereas incubation with insulin under serum-free conditions resulted in a dose-dependent increase in 11betaHSD1 activity (P < 0.05). Incubation with insulin-like growth factor I resulted in a similar pattern of 11betaHSD1 activity. Although neither testosterone nor androstenedione (5-200 nmol/L) affected 11betaHSD1 activity, incubation of myoblasts with dehydroepiandrosterone (500 nmol/L) resulted in a decline in 11betaHSD1 activity (P < 0.05). These data suggest that glucocorticoid hormone action in skeletal muscle is determined principally by autoregulation of GRalpha, GRbeta, and 11betaHSD1 expression by the ligand-binding GRalpha isoform. Additionally, insulin and insulin-like growth factor I regulation of 11betaHSD1 may represent a novel mechanism that maintains insulin sensitivity in skeletal muscle tissue by diminishing glucocorticoid antagonism of insulin action.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2000

Divalproex treatment for youth with explosive temper and mood lability: a double-blind, placebo-controlled crossover design.

OBJECTIVE: The authors sought to replicate open-label findings showing that specific criteria for explosive temper and mood lability identify disruptive youth who improve while receiving the anticonvulsant divalproex sodium. METHOD: Twenty outpatient children and adolescents (ages 10-18) with a disruptive behavior disorder (oppositional defiant disorder or conduct disorder) met the specific criteria for explosive temper and mood lability. They received 6 weeks of divalproex treatment and 6 weeks of placebo by random assignment. Independent evaluators blind to group assignment assessed response at the end of each phase. RESULTS: At the end of phase 1, eight of 10 subjects had responded to divalproex; zero of 10 had responded to placebo. Of the 15 subjects who completed both phases, 12 has superior response taking divalproex. CONCLUSIONS: This preliminary study replicates open-label findings showing that divalproex is an efficacious treatment for explosive temper and mood lability in disruptive children and adolescents.

Adolescent↗
PubMed1999

11 beta-Hydroxysteroid dehydrogenase: a link between the dysregulation of cortisol metabolism and hypertension.

Endocrine pathology is a well-recognised and important cause of human hypertension. Recent research has highlighted the role of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) in the development of certain forms of hypertension. This enzyme, which exists as two genetically unique isoforms, 11 beta-HSD1 and 11 beta-HSD2, is responsible for the interconversion of biologically active cortisol with its inactive 11-oxo derivative, cortisone. Congenital deficiency of 11 beta-HDS2 results in inappropriate activation of the renal mineralocorticoid receptor by cortisol, leading to hypertension, hypokalaemia and metabolic alkalosis. Several authors have postulated a link between changes in 11 beta-HSD activity and the development of certain forms of essential hypertension. The existence of endogenous inhibitors of the enzyme provides compelling evidence in favour of this hypothesis, but few have been able to demonstrate a clear link between inhibition of 11 beta-HSD2 activity and hypertension by this mechanism. Similarly, several authors have suggested a relationship between reduced placental 11 beta-HSD2 activity, low birth weight with high placental weight, and the development of hypertension in adulthood. However, no clear evidence to suggest a direct correlation between birth weight, placental weight and 11 beta-HSD2 activity has been demonstrated. While the role of 11 beta-HSD in the development of hypertension remains controversial, an understanding of the interplay of this enzyme with both mineralocorticoid and glucocorticoid receptors undoubtedly will yield data that will clarify this complex field.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

Imipramine treatment of opiate-dependent patients with depressive disorders. A placebo-controlled trial.

BACKGROUND: The literature is inconclusive on the role of antidepressant medications in treating drug dependence. Studies have either not focused on depressed patients or have selected patients with depressive disorders based on cross-sectional symptoms rather than a syndromal diagnosis. A clinical trial of an antidepressant was, therefore, conducted on drug-dependent patients with syndromal depression. METHODS: Patients receiving methadone hydrochloride maintenance treatment were selected if they met the criteria for a DSM-III-R depressive disorder that was chronologically primary, had persisted during a past abstinent period or was long-standing, and persisted during at least 1 month of stable methadone treatment. Subjects were randomized to a 12-week, double-blind, placebo-controlled trial of imipramine hydrochloride. A favorable response was defined as a Clinical Global Impression scale score for depression of 2 ("much improved") or 1 ("very much improved") and at least a 75% reduction in self-reported drug or alcohol use or abstinence. RESULTS: One hundred thirty-seven patients were randomized, and 84 completed a minimum adequate trial of at least 6 weeks. Among the 84 adequately treated patients, 57% (24/42) receiving imipramine were rated as responders compared with 7% (3/42) receiving placebo (P < .001). On measures of mood, there was a robust effect of imipramine. Imipramine was superior to placebo on some self-reported measures of substance use and craving, and mood improvement was associated with improvement in self-reported substance use. However, few patients achieved urine-confirmed abstinence. CONCLUSIONS: Imipramine was an effective antidepressant in patients receiving methadone who were selected via syndromal criteria for depressive illness. Imipramine may reduce substance abuse among patients whose mood improves; however, this effect was less robust.

Adult↗
PubMed1998

Placebo run-in period in studies of depressive disorders. Clinical, heuristic and research implications.

BACKGROUND: In spite of the virtually ubiquitous nature of the initial 10-day placebo run-in period (IPR) in drug trials, there is little empirical data establishing its relevance. METHOD: Data from 593 subjects were examined retrospectively to determine whether or not the prognosis of subjects minimally improved during the IPR was different to those who were unimproved. The IPR period was single-blind and was followed by a six-week double-blind phase in all studies. RESULTS: Twenty-six per cent of the subjects were minimally improved and 74% were unimproved. Approximately 10% of the subjects who were much improved were not followed systematically. Across a range of diagnosis, severity and chronicity subjects minimally improved (versus unimproved) after IPR had a more favourable prognosis whether assigned to drug or placebo. CONCLUSIONS: Change during IPR appears to be a meaningful predictor. Stratification should be considered in future antidepressant studies.

Adolescent↗
PubMed1998

Treatment of comorbid affective and substance use disorders. Therapeutic potential of anticonvulsants.

The authors examine the use of anticonvulsants/mood stabilizers to treat patients with substance use disorders. Although there is high comorbidity of bipolar and substance use disorders, there has been little research on the use of these medications to treat bipolar disorders in patients who also have a substance use disorders. However, symptoms of bipolar disorders, such as irritability and mood lability, may be difficult to distinguish from the effects of acute and chronic substance use; therefore, reliable diagnostic methods will need to be developed. Further, a new, hypothesized syndrome, Explosive Mood Disorder, is described that may be distinct from the bipolar spectrum. It is characterized by childhood onset of temper outbursts and irritable mood that persists into adolescence and adulthood, is connected to marijuana use, and responds to divalproex sodium. The authors review studies of prevalence, comorbidity, family history, longitudinal course, and placebo-controlled trials of anticonvulsant medications to evaluate the validity and treatment implications of this proposed entity.

Adolescent↗
PubMed1997

Divalproex treatment of disruptive adolescents: a report of 10 cases.

BACKGROUND: To report an open trial of divalproex sodium in 10 adolescents with chronic temper outbursts and mood lability. METHOD: Ten adolescents meeting screening criteria for chronic temper outbursts and mood lability were followed for 5 consecutive weeks on open divalproex sodium treatment. Temper outburst frequency and mood swings severity at pretreatment and posttreatment were compared by using paired t tests. Subjects continued to be followed to judge persistence of response. RESULTS: All subjects showed clear improvement at 5 weeks and maintained it during follow-up while taking medication. Rapid relapse and recovery occurred in 5 of 6 patients who discontinued and then resumed medication. CONCLUSION: Divalproex sodium may be helpful in teenagers who have explosive tempers and severe mood swings, and benefits may generalize to school and family life.

Adolescent↗
PubMed1996

Chronological milestones to guide drug change. When should clinicians switch antidepressants?

BACKGROUND: We attempt to identify the time when patients whose conditions are unimproved while receiving antidepressants are unlikely to respond and should have their treatment changed. METHODS: A total of 593 patients were studied. The course of treatment for patients was examined to determine the weeks at which patients who received drug therapy had a better chance of being rated as responders at the study end (week 6) vs patients who received placebo. RESULTS: At the end of week 3, 19 (32%) of the 59 patients who received drug therapy and 6 (10%) of the 57 patients who received placebo and who never minimally improved were rated as responders at week 6. For those who showed no improvement by week 4, the effects of drug therapy and the placebo were equal. Patients who received drug therapy and whose conditions were unimproved but who had been minimally improved at some point had a superior prognosis with drug therapy vs placebo until week 4. Of those unimproved at week 4 but minimally improved at some point previously, 20 (39%) of the 51 patients who received drug therapy vs 3 (8%) of the 36 patients who received placebo were rated as responders at week 6. Of the 75 patients who minimally improved while receiving drug therapy at the end of week 5, 33 (44%) had a chance of being rated a responder at the end of week 6 vs 9 (26%) of the 35 patients receiving placebo. CONCLUSIONS: Patients tolerant of an adequate dose, whose conditions have never been at least minimally improved by the end of week 4, should have their treatment regimen altered. These patients represented a minority of drug-treated patients in the sample studied (ie, 39/392 [10%]). Patients whose conditions minimally improve at some prior week but not after week 5 should have their treatment changed. Patients whose conditions minimally improve in week 5 should continue treatment until week 6.

Adolescent↗
PubMed1995

Bloodspot cortisol in mild asthma: the effect of inhaled corticosteroids.

Bloodspot cortisol, where finger pricked blood is applied to blotting paper, is suitable for repeated measurements in the home environment. The use of bloodspot cortisol measurements in children with asthma and the effect of inhaled corticosteroids on daytime cortisol concentrations were assessed. Twenty children with mild asthma were randomised to receive double blind either placebo or beclomethasone dipropionate 200 micrograms twice daily. Blood was taken by finger prick at home on waking, and treatment administered. Blood was then taken one hour after treatment, at lunchtime, and in the evening. The area under the curve (AUC) for the four time points was calculated as a composite index of daytime cortisol. Mean (SEM) bloodspot cortisols fell progressively over the day from 199.2 (15.6) nmol/l to 58.4 (8.9) nmol/l. Cortisol in the group treated with beclomethasone dipropionate was lower at all time points, but was significant only after treatment (mean (SEM) 120.9 (14.3) v 177.5 (21.0) nmol/l) and at lunchtime (mean (SEM) 82.7 (12.4) v 128.9 (12.6) nmol/l). AUC for the beclomethasone dipropionate treated group was also significantly decreased (mean (SEM) 317 (31.4) v 446 (29.7)). Beclomethasone dipropionate at a dose of 400 micrograms/day significantly suppresses the daytime cortisol profile.

Administration, Inhalation↗
PubMed1995

Medication use during psychoanalysis: a survey.

BACKGROUND: Historically, the psychoanalytic community has rejected the use of psychotropic medication, on the basis of the belief that using medication to suppress symptoms such as depression and anxiety would obstruct access to psychic conflict and thereby impede the progress of analytic treatment. However, it would appear that many psychoanalysis have reconsidered this point of view and are now combining medication with psychoanalytic treatment. This paper reports the first systematic survey of medication use in psychoanalysis. METHOD: Forty-five training analysts at the Columbia University Center for Psychoanalytic Training and Research were sent questionnaires that asked how many patients in analysis they had seen in the past 5 years and for details about any of those patients who had taken psychotropic medication. RESULTS: The analysts reported that in the past 5 years, 51 (18%) of 277 patients in analysis were also taking psychotropic medication. Most of these patients had been diagnosed with a unipolar mood disorder and were treated with some type of antidepressant. In 84% of patients (36 of 43) with a unipolar mood disorder who had been treated with medication, the psychoanalyst judged that both the mood disorder and the analytic process improved. CONCLUSION: The use of medication in combination with psychoanalysis is no longer an uncommon practice. Analysts who prescribe medication find that, in general, the effect is to enhance rather than undermine the psychoanalytic process.

Adult↗
PubMed1994

Duration of antidepressant trials: clinical and research implications.

The objective of our study was to demonstrate that additional antidepressant benefit occurs between weeks 4 and 6 in adult outpatients, even when dose is not increased. Response between weeks 4 and 6 was studied among depressed outpatients randomly assigned to imipramine, phenelzine, or placebo under double-blind conditions. Patients were selected for analysis only if they did not have a dose increase after the start of the fourth week of treatment (day 22). Eighty-eight patients met this condition. Conditional probability analysis was performed. Nonresponders to 4 weeks (28 days) of treatment had a significantly greater likelihood of responding by week 6 if they were on phenelzine rather than placebo. The same is probably true for patients on imipramine. In research and clinical care, 4 weeks is too short a trial of phenelzine to conclude a lack of efficacy. Four weeks is probably also too short a trial of imipramine.

Adult↗
PubMedDate not supplied

Evaluation and treatment of mood and anxiety disorders in opioid-dependent patients.

Mood and anxiety disorders are common and treatable but may cause considerable morbidity if left untreated. This is especially so in opioid-dependent individuals, for whom diagnosis is difficult and rehabilitation easily compromised. Clinicians need guidelines to distinguish the patient with an independent mood or anxiety disorder from the more common anxious or depressed addict who is withdrawing, intoxicated or reacting to a life crisis. This article reviews the current knowledge of diagnosis, clinical presentation, and prevalence of mood and anxiety disorders common among opioid-dependent patients. It attempts to identify features of a patient's history that distinguish truly independent disorders and proceeds to a discussion of treatment approaches for this subgroup.

Anxiety Disorders↗