Abnormal peripheral benzodiazepine receptor density associated with generalized social phobia.

BACKGROUND: Peripheral benzodiazepine receptors (PBRs) are involved in regulating stress responses. Abnormally low numbers of platelet PBRs have been found in patients with panic disorder, posttraumatic stress disorder, and generalized anxiety disorder, but not in patients with obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). The purpose of this study was to evaluate the PBR density on platelets from patients with generalized social phobia (GSP). METHODS: The density (Bmax) and dissociation constant (Kd) of platelet PBRs was determined for 53 medication-free patients with GSP and an equal number of control subjects (NC). RESULTS: The GSP group was found to have a significantly lower PBR Bmax than the NC group (GSP = 2764 +/- 1242 vs. NC = 4327 +/- 1850 fmol/mg protein, df = 1,100, F = 22.7, p = .00001). CONCLUSIONS: GSP shares this PBR abnormality with some other anxiety disorders but not with OCD or MDD. PBRs may play a role in the pathophysiology of some anxiety disorders.

Use of Lilium longiflorum, cv. ace pollen germination and tube elongation as a bioassay for the hepatocarcinogens, aflatoxins.

Although various animal tissues are used for bioassay of aflatoxins (B1, B2, G1, G2), a rapid bioassay dependent upon a plant part's response does not exist. Both pollen germination (G) and tube elongation (TE) were enhanced in a 3.0 mM KH2PO4 (K)-containing but AFB1-lacking, modified Dickinson's medium. The B1 did not affect G when K was withheld but K supplementation impaired G above 15 micrograms/ml B1. Without K, 5-20 stimulated but 25 and 30 micrograms/ml B1 inhibited TE which was suppressed by every B1 conc tested in K-containing medium. Addition of NaH2PO4(N) instead of K to medium did not promote G. Slight G stimulation occurred at 16.6 micrograms/ml mixed aflatoxins (MA) in medium lacking either K or N but low G inhibitions were observed with K or N. The MA at 33.3 micrograms/ml reduced G 2.5% in K's of N's absence and 26 or 17% in their presence. While K did not stimulate TE without MA, N did 26%. At 16.6 and 33.3 micrograms/ml MA, TE was reduced 19, 6, 19% and 24, 25, 31%, respectively, in control, K- and N- media. Pollen G and TE were markedly sensitive to G1. Significant inhibitions of Zea mays seed G were observed at 5.8 and 11.6 micrograms/ml B1 but not root elongation (RE) from 0.4-11.6 micrograms/ml. The MA (31.5 micrograms/ml) administered for 72-240 hr did not influence either Arachis hypogeae seed G or RE. However, imbibing 5 cultivars each of Avena sativa (65-117 hr) and Hordeum vulgare (39-89 hr) inhibited RE 4/15-62%. Thus, except for Z. mays, pollen G and TE appear to be more B1-sensitive than seed G and RE. But, the pollen bioassay is less sensitive than both certain animal bioassays (0.025 micrograms/ml) and analytical methodologies (10 pg.).

Cardiovascular effects of imipramine, fluvoxamine, and placebo in depressed outpatients.

BACKGROUND: The data presented represent cardiovascular parameters collected from one site of a larger, multicenter, double-blind, placebo-controlled, 6-week outpatient efficacy study of the serotonin uptake inhibitor fluvoxamine in depressed outpatients. METHOD: In this smaller study, we compared fluvoxamine (N = 17) to the prototypic antidepressant, imipramine (N = 14), and to placebo (N = 15). Specific parameters investigated were drug effects on postural pulse and blood pressure changes and ECG parameters including PR, QRS, and QTc intervals and ventricular heart rate. RESULTS: Fluvoxamine had few effects on measured parameters. Imipramine produced statistically significant changes on all measures; placebo had no effects on cardiac measures. CONCLUSION: Our data support that fluvoxamine, in a sample of healthy depressed outpatients, has little effect on cardiovascular function. Further study and clinical experience with this drug will be necessary before the full extent of its cardiac profile is known.

Effect of fluvoxamine, imipramine and placebo on catecholamine function in depressed outpatients.

Many of the specific serotonin reuptake inhibitors appear to have some effect on noradrenergic function. Fluvoxamine is one of the newer agents and its specificity has not been fully assessed. Depressed patients participating in a study comparing the efficacy of fluvoxamine with imipramine and placebo collected 24 hour urine samples (N = 38) and had plasma samples drawn (N = 38) prior to and after 6 weeks of double blind treatment. Urine samples were analyzed for 24 hour output of MHPG, VMA, NMN, MN and HVA. Plasma samples were analyzed for NE levels. Imipramine treatment produced a reduction in urinary MHPG, an increase in the ratio of NMN to MHPG plus VMA, and a trend towards an increase in plasma NE which was significantly different than the effects seen in the fluvoxamine and placebo groups. There was an additional finding in the imipramine group of a significant correlation between percentage change in plasma NE and clinical improvement. Fluvoxamine treatment, on the other hand, produced no clear effect on any measure of noradrenergic function and the antidepressant efficacy of fluvoxamine was unrelated to any noradrenergic variable. These findings lend support to the hypothesis that fluvoxamine does not have significant effects on noradrenergic function.

Evaluation of the efficacy, safety and physiological effects of fluvoxamine in social phobia.

There is no US Food and Drug Administration (FDA) approved treatment for social phobia although data suggest efficacy for several drug classes, including beta-blockers, benzodiazepines, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors (SSRIs). The SSRIs are particularly attractive due to their favourable tolerance and safety profile. An open label trial of fluvoxamine was conducted to evaluate its efficacy and safety in the treatment of social phobia (DSM-III-R) and to assess physiological changes that may accompany treatment. Fifteen non-depressed patients, aged 22-44 years (mean 31.6 years), entered the study. A 5-min performance task (public speaking simulation) preceded and concluded the active treatment period. Cardiovascular monitoring was performed during this time and blood sampled for plasma cortisol and steady-state plasma fluvoxamine concentration (at week 7). Ten patients (5 men and 5 women) completed an active 6 week treatment period of flexible dosing (50-150 mg/day). Five patients failed to complete the study due to drowsiness (n = 2), nausea (n = 1), or were lost to follow-up (n = 2). Analysis of clinical ratings indicated a statistically significant decrease in all scales from baseline to week 7 at the conclusion of the active treatment period. Clinical benefits were still evident at follow-up 1 week after drug discontinuation. Neither physiological effects nor plasma drug concentration correlated with clinical change. Fluvoxamine appeared to be effective and well tolerated in completers. Randomized clinical trials are needed to further demonstrate the efficacy of fluvoxamine in the treatment of social phobia.

Clinical psychopharmacy consultations: acceptance of recommendations on an adult inpatient psychiatric unit.

A retrospective chart review of consultations performed by a clinical pharmacist practicing in an adult psychiatric hospital was conducted. Data during the first 12 months of the service were collected from consultation reports, progress notes, physician's orders, laboratory data, and discharge summaries. Twenty-nine consultations were performed, resulting in a total of 135 recommendations. Of those, 125 were assessed and categorized. Of the recommendations, 113 (90.4%) were medication related and 12 (9.6%) were non-medication related. From the 125 recommendations, 99 (79.2%) were implemented and 26 (20.8%) were not. Particular categories of recommendations were also analyzed and had individual implementation rates ranging from 33.3% to 100%. Clinical pharmacists have previously documented their positive impact on patient care in a variety of settings, including psychopharmacy. The majority of recommendations made in this study were medication related with an overall implementation rate of 79%. This report illustrates the influence the clinical pharmacist has on the drug therapy of the psychiatric patient.

Regulatory pathways to the market: an overview.

This paper presents an overview of the U.S. Food and Drug Administration's regulatory requirements for introducing medical device and diagnostic products into commercial distribution in the United States. For any specific product, the requirements vary depending upon the product's associated risks, classification, and when it or a similar product was first introduced into commercial distribution. Regulatory pathways available and/or required for a manufacturer to introduce a medical product into the U.S. marketplace are outlined.

Pharmaceutical services in a medical screening clinic.

Pharmaceutical services in a medical screening clinic are described. Services provided include medication refills, patient education and medication histories. During the first year 1,067 patients were interviewed, evaluated and received these services from the pharmacist. The majority of these patients were seen for medication refills. A clinical assessment was made by the pharmacist of the current drug therapy, evidence of new or drug-related problems, and compliance with medication regimens. One hundred seventy-six patients were found to be receiving inappropriate drug therapy, 69 patients were found to have drug-related problems and 248 patients were found to be noncompliant with their drug regimens. Patients received 1,633 refills and 24 new prescriptions. One hundred fifty patients were refused refills because the medications were being abused or were not indicated. Many patients (564) received extensive education about their medications and diseases. One hundred eleven laboratory tests were ordered and 323 clinic appointments were made. The pharmacist is providing services which are an asset to both patients and other members of the health care team.

The clinical usefulness of lithium as an antidepressant.

Much attention has been directed toward the use of lithium in bipolar depressive illness (manic-depressive illness), but fewer studies have evaluated lithium's efficacy in unipolar depressive disorders. This paper critically reviews the literature dealing with the use of lithium for the treatment of acute unipolar depression as well as for prophylaxis against future depressive episodes. Differences in study design, entry criteria, serum lithium level, dose, patient population, and diagnosis are highlighted; these variations help explain some of the controversy surrounding the use of lithium in unipolar depression. The available information indicates that lithium should be seriously considered as an effective alternative for the treatment of unipolar depression when other antidepressant medications are ineffective or contraindicated.

Lithium side effects in the medically ill.

OBJECTIVE: This review will include the general pharmacology of lithium and discuss its effects on various organ systems, with emphasis on the medically ill patient as well as the geriatric patient with multiple medical problems. METHODS: A full literature review on the side effects of lithium was performed. Attention is focused on the medically ill and possible drug interactions. RESULTS: This review points to the numerous problems which can result in toxicity in the medically ill or the geriatric patient. CONCLUSION: Serious side effects can be avoided with proper drug monitoring and knowledge of potential drug interactions.

Venlafaxine: a structurally unique and novel antidepressant.

OBJECTIVE: To introduce the new antidepressant venlafaxine. Basic pharmacokinetic data and clinical trials are reviewed, as well as adverse reactions, drug interactions, dosing guidelines, and therapeutic considerations. The article also discusses several pharmacotherapy issues and how venlafaxine compares with other available antidepressants. DATA SOURCES: A MEDLINE search was used to identify pertinent literature, including reviews. STUDY SELECTION: As this is a relatively new agent, all available clinical trials were reviewed. DATA EXTRACTION: All clinical trials that were available prior to submission for publication were reviewed. Preliminary trials and unpublished reports were not reviewed. DATA SYNTHESIS: Venlafaxine hydrochloride is a structurally novel agent that has recently been approved in the US for the treatment of depression. This unique antidepressant blocks neuronal reuptake of norepinephrine, serotonin, and, to a lesser extent, dopamine. Venlafaxine and its major active metabolite, O-desmethylvenlafaxine, exhibit linear kinetics with an elimination half-life of 5 and 11 hours, respectively. Venlafaxine has been evaluated in 7 clinical trials for the treatment of depression. These have consisted of 2 open trials, 3 double-blind, placebo-controlled trials, and 2 double-blind trials where venlafaxine was compared with trazodone and imipramine. All 7 trials have established efficacy for venlafaxine using standard psychiatric rating scales to measure change of depressive symptoms. The usual daily dosage ranges from 75 to 225 mg/d in 2 to 3 divided doses, with a maximum daily dosage of 375 mg/d. The drug's adverse effect profile differs somewhat from other more specific serotonin reuptake inhibitors in that it appears to cause dry mouth, somnolence, and elevated blood pressure as well as nausea, headache, and dizziness. CONCLUSIONS: Although venlafaxine has recently become available for use as an antidepressant in the US, few clinical trials have been conducted to help the practitioner evaluate its place in the treatment of depression. There are no comparative trials of venlafaxine with the serotonin specific reuptake inhibitor antidepressants, which are rapidly becoming the newest comparative standard. The clinical place for venlafaxine in the treatment of depression has yet to be determined.

Study of aggregate formation in region of separated blood flow.

The formation of platelet aggregates which embolize to the peripheral circulation has previously been noted as a significant deleterious effect resulting from both intra- and extracorporeal artificial circulatory devices. Utilizing the stagnation point flow experiment, which permits visualization during flow of aggregate formation on first contact of blood with an artificial surface, the formation of freely floating aggregates has been observed in separated flow regions. Embolization from the separated flow has also been noted. Comparison of observed growth rates with a hydrodynamic model suggests that sufficient activation has occurred within the separated region so that platelets stick on virtually every collision. Some criteria are also suggested which correlate with the flow conditions affecting aggregate formation. At high flow rates, where freely floating aggregates do not form, significant surface thrombi are found.

Substance abuse and bipolar affective disorder.

This interview study was conducted to explore the onset, course, and features of bipolar affective disorder complicated by substance abuse. Forty-four patients with a diagnosis of bipolar affective disorder were interviewed using the Structured Clinical Interview for DSM-III-R, Hamilton Rating Scale for Depression, Young Mania Rating Scale, and a questionnaire concerning psychiatric history. Current substance users averaged twice as many hospitalizations for mood problems. The age of onset of mood problems for substance users was significantly earlier than that of the nonusers (p < or = .05). Substance users were four times as likely to have other comorbid axis I disorders (p < or = .05) and twice as likely to have dysphoric mania at time of interview. This preliminary study suggests that individuals with bipolar affective disorder complicated by substance abuse may have more hospitalizations, a higher incidence of dysphoric mania, earlier onset of mood problems, and more comorbid axis I disorders.

Pharmacologic management of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is an intriguing, difficult problem characterized by anxiety-producing intrusive thoughts and performance of anxiety-reducing rituals. Current evidence suggests that OCD may be associated with dysregulation of serotonin and dopamine neurotransmission. Numerous early studies involving the serotonin-specific reuptake inhibitor clomipramine led to the formulation of this hypothesis. Positive results with clomipramine initiated further research with other serotonin-specific reuptake inhibitors, such as fluoxetine, fluvoxamine, sertraline, and serotonergic agents such as buspirone and trazodone. Findings from a number of clinical trials suggest that drugs that inhibit serotonin reuptake or affect serotonergic transmission in other ways are of clear benefit in the treatment of OCD. These drugs may be more effective for obsessive thoughts than for compulsive rituals. Effective pharmacotherapy can dramatically decrease obsessive-compulsive symptoms and improve the patient's quality of life.

Improvement in antiepileptic drug levels following reduction of intervals between clinic visits.

Antiepileptic drug levels (AEDLs) may reflect how well patients adhere to prescribed medical regimens. Of 30 patients on stable drug regimens AEDLs were increased in 33% by decreasing clinic visit intervals from a mean of 3.4 months to 1.1 months. The testing situation was applied to patients who had AEDLs in the "therapeutic range" (n = 15) as well as those with one or more AEDLs below "therapeutic range" (n = 15). In the latter group 73% of patients showed improvement in AEDLs. Although a less reliable parameter, verbally reported seizure frequencies were also improved. Overall, the reduction in clinic visit interval could be expected to yield improvement in 46 to 80% (confidence interval = 95%). These patients responded equally well to physician and non-physician practitioners. This technique may be useful as an intervening measure for those patients who are noncompliant.

Effects of polymer surface molecular structure and force-field characteristics on blood interfacial phenomena.

To quantify the effects of major surface structural factors influencing interfacial reactions induced by polymers in native blood, model surfaces of solvent-cast films of two analogous poly(ether urethanes) and three homologous polyamides (nylon 4, 6/6, and 12) were exposed ex vivo to canine blood under the well-defined hemodynamic conditions of the Stagnation Point Flow Experiment. The selected surfaces allow for incremental changes in properties and were characterized by their "Composite Surface Free ENergy Function," gamma'S, which describes the surface force field as the sum of the mean dispersion (gammaSd) and polar (gammaSp) contributions and is computed from wettability spectra obtained with ultrapure diagnostic liquids. Blood interfacial effects were measured by the shear-limited diameter of the white cell circle formed around the stagnation point, the flow parameter at which symmetric aggregation occurred, and the surface-number density of platelets, [P s], remaining adherent under fixed conditions. At identical flows, within each group of polymers, both the WBC-circle diameter and [P s] scale with gamma Sp/gamma'S, implying that 1) only the magnitude but not the interaction mechanism varies as a function of incremental structural and surface changes, 2) the primary determinant of surface-induced effects is the polar force contribution, and 3) the magnitude of gamma'S is secondary if gammaSd/gamma'S is sufficiently great.

A prediction model for identifying alcohol withdrawal seizures.

A retrospective review of alcohol withdrawal seizures was performed at a private chemical-dependence treatment facility to help identify patients who were at high risk for having a seizure. Patients were identified by two means: controlled substance records were reviewed to determine patients having received intramuscular phenobarbital, and patient charts were reviewed for all patients with a discharge diagnosis of a seizure disorder. Two thousand and one patient records were reviewed; alcohol withdrawal seizure patients were identified. Twenty-eight randomly selected nonseizure patient records served as controls. The statistical test consisted of a discriminant function analysis. The data yielded a statistically significant predictive model for alcohol withdrawal seizures based on six interdependent patient variables which will be helpful in treating future patients undergoing alcohol withdrawal.

Impact of regulations on artificial organs research.

From a research perspective, some of the primary problems created by the FDA regulations include: the amount of time necessary to comply with the regulations and to obtain FDA and IRB review of the studies. The cost of such delays may be great in terms of statistical death. Lack of understanding of the regulations on the part of investigators. Escalated costs and extra restrictions on the use of animals. Benefits of the regulations appear to be: better preclinical testing performed prior to initiating clinical trials, and improved testing protocols, both of which may result in lower risks to patients.

Bupropion-SR in treatment of social phobia.

A 12-week, open label flexible dosing study was conducted to evaluate the efficacy of bupropion-SR in the treatment of generalized social phobia. The primary outcome measures include the Clinical Global Impression of Improvement (CGI-I) and the Brief Social Phobia Rating Scale (BSPS). A total of 18 subjects were enrolled. Five of the ten subjects who completed all 12 weeks were considered as responders. Response to treatment was defined as a CGI-I score of 1 or 2, ("much improved" or "very much improved," respectively) and a > 50% decrease in BSPS score. The final doses for the completers ranged between 200 and 400 mg/day (mean 366 +/- 68 mg/day). The medication was generally well tolerated. Findings from this open-label trial suggest that bupropion-SR may be useful in treating generalized social phobia.