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Biomedical subjects

M V Rudorfer

Publications and source records attributed to M V Rudorfer.

At least 19 recordsLinked to original sources
PubMed1992

Monoamine oxidase inhibitors: reversible and irreversible.

Coincident with and in part fueling advances in diagnostic nosology and drug development, the recent resurgence of interest in monoamine oxidase inhibitors (MAOIs) is reviewed. Accidentally discovered nearly 40 years ago as the first true antidepressants, the MAOIs soon fell into disfavor due to concerns about toxicity and seemingly lesser efficacy compared with the newer tricyclic compounds. Now that we have better understanding of the nature of the hypertensive and hyperpyrexic interactions of MAOIs with other substances, these medications have assumed a role in the treatment of nonendogenous depressive and anxiety syndromes, especially in operationally defined "atypical depression." The discovery of two MAO isoenzymes has resulted in a new generation of selective inhibitors in the search for enhanced efficacy (i.e., clorgyline) or safety (i.e., l-deprenyl). Most promising is the emerging class of reversible selective MAO-type A inhibitors, such as moclobemide, which combine antidepressant potency with freedom from the risk of dangerous tyramine-type adverse interactions.

Depressive Disorder↗
PubMed1991

Hypothalamic--pituitary--adrenal axis and monoamine transmitter activity in depression: a pilot study of central and peripheral effects of electroconvulsive therapy.

Central and peripheral measures of hypothalamic--pituitary--adrenal (HPA) axis and monoamine neurotransmitter activity were assessed in 8 depressed patients during a medication-free period and again after completion of a course of electroconvulsive therapy (ECT). Seven patients responded fully to ECT. At baseline there was corresponding activation of the HPA and noradrenergic systems, with apparent elevation in cerebrospinal fluid (CSF) concentrations of corticotropin-releasing hormone (CRH) in some patients. Neither CRH nor adrenocorticotropin (ACTH) in CSF changed significantly after ECT, with a mean 10% decline in CSF CRH. Urinary free cortisol (UFC) excretion was high both before and after treatment. Although peripheral noradrenergic hyperreactivity at baseline appeared to normalize with ECT, CSF concentrations of the principal norepinephrine metabolite, 3-methoxy-4-hydroxyphenyl-glycol (MHPG) were unaffected and remained correlated with CSF CRH. In contrast, there were increases in the CSF levels of the main metabolite of serotonin in half the patients.

Adult↗
PubMed1991

The mechanisms of action of lithium. I. Effects on serotoninergic and noradrenergic systems in normal subjects.

The effects of 2 weeks of lithium carbonate administration at therapeutic plasma levels were examined in 11 normal volunteers. Serotoninergic function before and after lithium administration was assessed using low-dose intravenous clomipramine hydrochloride challenge, while urinary and plasma metabolites of norepinephrine (NE) were used to assess noradrenergic systems. Long-term lithium administration in normal subjects did not significantly or consistently enhance serotonin-mediated neuroendocrine responses but did increase measures related to neuronal release of NE. No statistically significant effects of lithium on prolactin, corticotropin, or cortisol responses to serotoninergic challenge could be detected. The probability of a type II error was assessed, and a doubling of prolactin level was unlikely to have been missed, although more modest increases (less than 75%) could have been overlooked. After 2 weeks of lithium administration, there were significant increases in 24-hour urinary excretion of NE, normetanephrine, and fractional NE release, compatible with increased neuronal release of NE and a lithium-induced subsensitivity in alpha 2-adrenergic receptor function. These changes were not statistically significant after 1 week of administration, suggesting that increased NE release is characteristic of long- rather than short-term lithium administration. Since previous reports have demonstrated enhanced prolactin responses after short- but not long-term lithium use, the present study points to temporal specificity in lithium's effects on both serotoninergic and noradrenergic function. Lithium's effects on NE release were consistent but small (a 16% increase), while its effects on serotoninergic responses were larger (a 50% increase in prolactin responses) but quite inconsistent, suggesting that neither of these systems is the primary site of action of lithium.

Adrenocorticotropic Hormone↗
PubMed1991

Signal transduction modulation by lithium: cell culture, cerebral microdialysis and human studies.

Considerable evidence suggests that signal transduction pathways are targets of lithium (Li) action. A number of investigators have reported that Li attenuates both adenylate cyclase (AC) activity and phosphoinositide (PI) turnover in rodents and in humans, thus "dampening" these systems. We have studied selected components of these second-messenger systems in a series of clinical and preclinical investigations. To overcome confounding effects of alterations in mood state, we examined AC activity and G-protein ribosylation in peripheral blood cells from 10 healthy volunteers, prior to and following 14 days of Li administration. Basal and postreceptor [cesium fluoride (CsF) or Gpp(NH)p] stimulated AC activity were unaffected in lymphocytes. In contrast, both basal and stimulated AC activity in platelets were significantly augmented, compatible with an attenuation of Gi function. Ribosylation of platelet Gs by cholera toxin was unchanged, whereas that of Gi by pertussis toxin (PT) was increased. Given that undissociated G protein is the preferred substrate for PT, our results suggest that Li interferes with subunit dissociation and the subsequent activation of Gi. To determine if Li has similar effects on Gi in the central nervous system, we measured extracellular (EC) cyclic adenosine monophosphate (cAMP) in rat brain by in vivo microdialysis, revealing a dose-dependent increase in cAMP by norepinephrine (NE) antagonized by propranolol. Chronic (4-week) Li doubled basal EC cAMP, while decreasing the fractional response to 100 microM NE. Thus, using in vivo microdialysis, we observed the reported reduction in NE-stimulated AC activity, but only as a function of elevated basal cAMP. Increased basal AC activity has been observed following chronic Li in both humans and rat tissues but generally has not been considered relevant. The PI generating system is another proposed major target for Li that we have studied using an in vitro cell culture model of peripheral blood cells. Chronic (6-day) exposure of neutrophil-like HL60 cells to 1 mM LiCl did not affect agonist fMet-Leu-Phe (fMLP) induced PI turnover. In contrast, Li attenuated both agonist and phorbol ester stimulated Na+/H+ exchange, suggesting reduced protein kinase C (PKC) function. Western blot analysis revealed altered levels of PKC in both membrane and cytosolic fractions. The functional consequences of these complex effects on the two major signal transduction pathways and their interactions in the intact living organism remain to be elucidated.

Adult↗
PubMed1991

Dosage regimen design for cyclic antidepressants: a review of pharmacokinetic methods.

One of the difficulties in pharmacotherapy of depression is the frequent need to make several dosage titrations before reaching the optimal therapeutic dosage. This problem has led to several experimental approaches for predicting a stable antidepressant maintenance dose from plasma concentration data collected shortly following a test dose. The theoretical basis for these methods is reviewed along with the results of clinical trials. It is concluded that accurate steady-state concentrations of cyclic antidepressants can be predicted from kinetic analysis of plasma concentrations obtained early in therapy. The most applicable drug for prospective dosing methods is nortriptyline with its widely accepted therapeutic plasma concentration range. Other drugs that also have substantial evidence for predicting the optimal dose from an early point in therapy include desipramine and imipramine. Predictive dosing methods are easily applied in the inpatient setting. Multiple data points obtained between 12 and 48 hours after the first dose are likely to give accurate predictions and provide clinically useful information. More widespread application of predictive approaches to dosage regimen design of antidepressant pharmacotherapy may lead to reduced hospitalization and cost savings.

Antidepressive Agents, Tricyclic↗
PubMed1991

Acute noradrenergic effects of desipramine in depression.

As a probe of the noradrenergic system in depression, single oral doses of the tricyclic antidepressant desipramine (100 mg) and placebo were administered to unipolar and bipolar depressed patients and healthy volunteers. Plasma concentrations of norepinephrine (NE) were determined 2-3 hours after dosing, with subjects in supine and upright positions. On the placebo day plasma NE was low in a subset of bipolar patients; both groups of depressives demonstrated an exaggerated increase in plasma NE upon standing. After desipramine dosing, the orthostatic procedure resulted in even greater relative increments in plasma NE in both patient groups, with no change in volunteers. These data are consistent with noradrenergic dysregulation in depression.

Administration, Oral↗
PubMed1989

Antidepressants. A comparative review of the clinical pharmacology and therapeutic use of the 'newer' versus the 'older' drugs.

Supplementing but not supplanting the original series of tricyclic and monoamine oxidase (MAO) inhibitor compounds, a new generation of antidepressant medications has been developed and marketed throughout the past decade. Constituting a more diverse group of drugs than the standard agents, the newer drugs in general have more selective acute biochemical actions (reuptake blockade of a single neurotransmitter, inhibition of 1 subtype of MAO), enabling more precise targeting of symptoms and avoiding common antidepressant-associated side effects, especially anticholinergic and cardiovascular effects. Moreover, a number of recent additions to this group, such as bupropion and ademetionine (S-adenosyl-methionine), incorporate novel mechanisms of action, challenging previous concepts of how antidepressants work, and offering opportunities for research into the pathophysiology of mood disorders. Caution in prescribing the newer antidepressants must be applied, however, as recent experience, e.g. with nomifensine, suggests that unforeseen toxicities may not appear until a medication has been in use for several years.

Animals↗
PubMed1988

Bupropion in depression. I. Biochemical effects and clinical response.

We studied the biochemical effects of bupropion hydrochloride, a unicyclic antidepressant, in 11 depressed patients. Plasma homovanillic acid level increased significantly in patients who had poor responses to treatment but not in patients who obtained good clinical responses. Although bupropion is characterized preclinically as a weak dopamine reuptake inhibitor without appreciable effects on norepinephrine (NE) reuptake, it reduced whole-body NE turnover without altering plasma NE levels at rest and following orthostatic challenge. There was a trend toward a reduction in cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol and homovanillic acid concentrations following bupropion treatment, although these changes did not achieve statistical significance. Reduction in whole-body NE turnover has now been described for six disparate antidepressant treatments. Poor clinical outcome following treatment with bupropion may be related to perturbations in dopaminergic systems.

Adult↗
PubMed1988

Bupropion in depression. II. The role of metabolites in clinical outcome.

We studied the steady-state pharmacokinetics of bupropion hydrochloride, a unicyclic aminoketone antidepressant, in depressed patients. The metabolites hydroxybupropion (HB), threohydrobupropion, and erythrohydrobupropion predominated over the parent compound in plasma and cerebrospinal fluid at steady state. Plasma concentrations of each metabolite correlated with cerebrospinal fluid concentrations. Higher plasma metabolite concentrations were associated with poor clinical outcome. This relationship was most striking with HB; plasma HB levels were greater than 1250 ng/mL in all five nonresponders and less than 1200 ng/mL in all seven responders. Plasma HB levels correlated with postreatment plasma homovanillic acid levels. High levels of bupropion metabolites may be associated with poor clinical outcome due to toxic effects involving dopaminergic systems. Alternatively, a curvilinear dose-response relationship may exist for bupropion metabolites. Future studies should explore the clinical utility of plasma metabolite measurements in enhancing the efficacy of treatment with bupropion.

Adult↗