Pharmacokinetics of abecarnil in patients with renal insufficiency.

OBJECTIVE: To characterize the pharmacokinetics of a single 5 mg oral dose of abecarnil in subjects with varying degrees of renal impairment. METHODS: Twenty-six subjects were enrolled in this open-label parallel-group study. Ten subjects had normal renal function (NRF; creatinine clearance [CLCR] > or = 85 ml/min/1.73 m2), six subjects had mild to moderate renal insufficiency (MMRI; CLCR between 25 and 73 ml/min/1.73 m2), and 10 subjects had severe renal insufficiency (SRI; CLCR < or = 10 ml/min/1.73 m2). Abecarnil plasma concentrations were determined by means of HPLC, and plasma protein binding was determined by use of ultracentrifugation. Pharmacokinetic parameters were obtained with use of model-independent and model-dependent methods. RESULTS: In subjects with SRI, area under the concentration-time curve and maximum plasma concentration were reduced by 36% and 31%, respectively, compared with demographically matched subjects with NRF. The apparent total body clearance in the NRF, MMRI, and SRI groups was 13.0 +/- 6.89, 12.9 +/- 3.64, and 25.0 +/- 13 ml/min/kg, and the apparent volume of distribution was 14.0 +/- 3.78, 12.8 +/- 2.4, and 19.4 +/- 5.76 L/kg, respectively (mean +/- SD). The patients with SRI had a significantly lower protein bound fraction than subjects with NRF (0.850 +/- 0.077 versus 0.948 +/- 0.023). Despite an increase in the free fraction of abecarnil (f(u)), there was no significant change in the apparent unbound total body clearance and unbound volume of distribution between the SRI and NRF groups. The anticipated full effect of the increase in f(u) among the patients with SRI was not realized and suggests that the f(u) in tissue may be increased in patients with SRI. CONCLUSION: Dose adjustment will need to be made on the basis of titration to the desired clinical response and tolerability in patients with SRI just as in subjects with NRF.

The use of beta-adrenergic blocking agents in anxiety disorders and schizophrenia.

In the 1960s, several studies reported that propranolol and other beta-blocking drugs appeared especially useful in patients with physical symptoms of anxiety. However, subsequent reports produced conflicting findings, and at this time the efficacy of propranolol in anxiety disorders is not clearly established. Propranolol's utility in anxiety states may be entirely restricted to those anxiety patients whose physical symptoms have not adequately responded to benzodiazepine therapy. This places the beta-blockers among the least useful drugs in treating anxiety disorders. A major problem in assessing propranolol's antianxiety properties has been a virtual lack of well-designed studies addressing the issue; the studies reviewed here contained a surprising number of study design problems. Several guidelines regarding study design are included to assist the reader in evaluating studies of antianxiety agents. High dose (e.g., 2,000 mg) propranolol may have a role as an alternative to traditional antipsychotic therapy in neuroleptic-resistant patients. During the last decade a number of studies have demonstrated symptomatic improvement in schizophrenic patients using propranolol alone or combined with neuroleptics. However, four recent double-blind reports have failed to replicate this finding. Future research should focus on possible identification of propranolol-responsive patients and their characteristics. The use of propranolol and other beta-blockers in schizophrenia should remain in the research or medical center setting.

Beta-blockers in anxiety disorders.

Studies evaluating the antianxiety and antipanic properties of beta-blockers do not support their routine use in treating either generalized anxiety disorder or panic disorder. The use of propranolol for anxiety disorders accompanied by physical symptoms, especially cardiovascular complaints, may be effective in some patients when combined with benzodiazepines or perhaps in some non-responders to conventional treatment. Better designed studies are needed to evaluate the exact role of beta-blocking agents in treating anxiety. The efficacy of propranolol in patients with panic disorder has not been widely researched, but preliminary results have not been encouraging. Propranolol may provide symptomatic relief in some patients with residual somatic complaints (i.e., palpitations and tachycardia), when combined with the patient's ongoing drug regimen. Because beta-blockers may induce depression, they should be used cautiously--if at all--in panic patients with concurrent depressive illness.

Alprazolam versus imipramine in depressed out-patients with neurovegetative signs.

The purpose of this study was to compare the safety and efficacy of a relatively new antidepressant drug, alprazolam (a triazolobenzodiazepine) with imipramine in the treatment of 60 depressed symptomatic volunteers. Eligible patients were randomly assigned after a 1-week washout to one of the medications and followed for 6 treatment weeks. Contrary to the earlier report of Feighner et al. (1983), who found alprazolam superior to imipramine and placebo, but consistent with Rush et al. (1985) we find imipramine superior in efficacy to alprazolam on a variety of symptoms. Both the present study and Rush's study employed patients with signs indicative of response to tricyclics. Feighner's patients may have been the type who tend to be less responsive to tricyclics but may be more responsive to alprazolam. Some of our data also show that alprazolam may have a more advantageous effect in the early weeks of treatment but is overtaken in subsequent treatment weeks by imipramine.

Dexamethasone suppression test in diagnosis of depressive illness.

Neuroendocrine abnormalities present in depressive illness and use of the dexamethasone suppression test (DST) in diagnosing depression are reviewed. The coexistence of neuroendocrine disturbances and depressive illness may be explained by a central nervous system neurochemical abnormality. Norepinephrine appears to inhibit hypothalamic corticotropin-releasing factor, thus decreasing ACTH secretion by the pituitary and, in turn, cortisol secretion by the adrenal glands. Thus, a deficiency in brain norepinephrine may lead to both depressive symptoms and increased adrenal cortisol production. Episodes of cortisol secretion are longer and more frequent in depressed patients, and the circadian rhythm of cortisol release is altered. Dexamethasone does not suppress plasma cortisol levels in depressed patients as compared with normal subjects. Abnormal DST results were obtained in 40-70% of inpatients and 20-50% of outpatients diagnosed as having unipolar primary depression or major depressive illness. The incidence of abnormal DST results in most nondepressed psychiatric patients is comparable with that in normal subjects. DST results do not distinguish between unipolar and bipolar depression but may differentiate primary from secondary depression. Depressed patients with abnormal DSTs responded positively to drug treatment. DST nonsuppressors responded more favorably to norepinephrine-reuptake blockers, while DST suppressors preferentially improved with serotonin-reuptake blockers. Normalization of DST response has been associated with clinical improvement. Certain drugs, a number of psychiatric conditions, and several major physical illnesses may alter DST response. The DST is a commonly used and practical tool in evaluating depressive illness; however, its diagnostic value in depressed outpatients and elderly depressed patients is not clear.(ABSTRACT TRUNCATED AT 250 WORDS)

Adverse reactions to five new antidepressants.

Postmarketing adverse drug reaction reports for amoxapine, maprotiline hydrochloride, and trazodone hydrochloride and premarketing adverse drug reaction data for bupropion hydrochloride and nomifensine maleate are reviewed, and the role of the new agents in the management of depressive illness is discussed. Nomifensine was withdrawn from markets worldwide because of reports of serious hypersensitivity reactions, especially hemolytic anemia, and marketing of bupropion in the United States was delayed after seizures occurred in bulimic patients in clinical trials. Amoxapine and maprotiline, when taken in overdose attempts, are more toxic and cause more serious central nervous system reactions than the standard tricyclics. Acute renal failure and an increased mortality rate are associated with amoxapine overdose. Amoxapine causes several acute and chronic untoward neurologic and endocrine reactions not commonly associated with the standard tricyclics. For maprotiline and bupropion, maximum doses have been established because of dose-related seizures. Trazodone has minimal effect on cardiac conduction; its main cardiovascular effects are hypotension, orthostasis, and dizziness. The trazodone package insert has been revised to warn of priapism; patients with prolonged or inappropriate penile erections are instructed to discontinue the drug and notify the physician. Serious cardiovascular and neurologic toxicities are rare with trazodone overdose. Of the newly marketed antidepressants, only trazodone offers some advantages over the tricyclic and tetracyclic agents in the areas of side effects and toxicities. The number and type of patients exposed to a new drug during clinical trials is too small for detection of rare but potentially serious adverse effects.

Current concepts in clinical therapeutics: anxiety disorders, Part 1.

The diagnosis, epidemiology, classification and clinical presentation, pathophysiology, and treatment of anxiety disorders are reviewed. Anxiety disorders, among the most common mental disorders, must be differentiated from medical diseases with anxious symptoms. A complete physical and mental status examination, as well as a thorough knowledge of the patient's medical, psychiatric, and drug history are required. Epidemiologic studies indicate an incidence of 4-8% in the United States. There are four categories of anxiety disorders: phobic disorders, anxiety states, posttraumatic stress disorders, and atypical anxiety disorders. Several psychoanalytic, behavioral, and cognitive theories have been advanced to explain the pathophysiologic mechanisms causing anxiety disorders. Of most interest are the biological theories involving the catecholamine neurotransmitter norepinephrine and the benzodiazepine receptor. Proper treatment for anxiety disorders involves nonpharmacologic and pharmacologic approaches. The benzodiazepines are widely used and are the mainstay of drug treatment for patients with situational anxiety and generalized anxiety disorder. However, problems with sedation, complications of drug withdrawal, and patients' fear of drug dependency may limit clinical usefulness. Buspirone is the first nonbenzodiazepine anxiolytic to be introduced in the United States in more than 25 years. Its unique role in treating anxiety, compared with the benzodiazepines, may include less sedation, minimal drug abuse potential, and fewer withdrawal symptoms upon drug discontinuation. Nonpharmacologic therapy is used extensively in the treatment of phobic disorders (simple and social phobia). Important advances in the diagnosis and treatment of anxiety disorders have been made. An accurate diagnosis is essential for optimal management. Unfortunately, many anxious patients do not seek treatment and some do not receive the most appropriate treatment.

Residency in mental-health pharmacy with a research component.

A 12-month postdoctoral specialized residency program in mental-health pharmacy practice with a psychopharmacology research component is described. The resident spent approximately four hours a day in clinical practice and in research activities in the inpatient setting; 10 hours per week in clinical research activities in an ambulatory patient setting; and 10 hours per week in teaching and scholarly activities. The resident was a member of a psychopharmacology research team that also included a research psychiatrist, a nurse, and two psychiatric medical residents at an adult acute-care site. The resident prepared a review of the preclinical evaluations of each investigational drug and participated in the initial screening of study patients. The resident was responsible for patient consent procedures, coordinating clinical evaluations, and scheduling necessary laboratory tests. As a member of the clinical team, she was also responsible for obtaining medication histories, monitoring and reporting adverse drug reactions, maintaining accurate dosage records, and completing the appropriate rating scales in the clinical evaluation of patients. In the ambulatory setting, the resident participated in the outpatient management of study patients. The resident learned to assess patient's clinical progress, maintain progress notes, write medication orders and administer medications in acute situations, maintain individual treatment plans, follow approved drug research protocols, and provide a program of education for patients and families when necessary. In addition, the resident was involved in educational programs for pharmacy students. This training program enables the pharmacist to gain experience in drug research studies, clinical practice, and pharmaceutical education, while contributing to psychopharmacology research.

Effect of estrogens on the dexamethasone suppression test in nondepressed women.

It is often suggested that estrogens may cause false-positive dexamethasone suppression test (DST) results. In this study of nine healthy, non-depressed women, DSTs were performed at baseline, immediately following administration of 21 days of oral contraceptives containing either 50 or 80 micrograms of mestranol (a synthetic estrogen) in combination with 1 mg of norethindrone (a synthetic progesterone), and 1 month after discontinuing the oral contraceptives. All subjects had post-dexamethasone cortisol levels less than or equal to 5 micrograms/dl during the study with the exception of two subjects in the mestranol 80 microgram group who had positive DSTs immediately following oral contraceptive administration; one of these subjects continued to have a positive DST 1 month later. DST results should be interpreted with caution if high dose estrogens are taken concurrently or have been recently discontinued.

Effect of ibuprofen on lithium plasma and red blood cell concentrations.

The effect of ibuprofen on steady-state lithium plasma and red blood cell concentrations was studied in 11 normal volunteers. During the seven-day control phase, sustained-release lithium carbonate 450 mg was administered every 12 hours. Lithium plasma and red blood cell concentrations were determined on days 5, 6, and 7. During the treatment phase (days 7-15), ibuprofen 400 mg was administered four times a day concurrently with lithium. Lithium plasma and red blood cell concentrations were obtained on days 14, 15, and 16. Multiple blood samples were obtained over a 12-hour period on days 6 and 15. Urine samples were collected from six subjects. The mean minimum lithium concentration increased 15% when ibuprofen was added. Mean maximum lithium concentration, area under the curve, red blood cell concentrations, and the lithium red blood cell to plasma ratio were significantly higher during the treatment phase. Mean lithium total body and renal clearance values were significantly lower during the treatment with ibuprofen. The administration of ibuprofen can increase steady-state plasma lithium concentrations and decrease lithium clearance.

Single-dose bioavailability of two extended-release lithium carbonate products.

The single-dose bioavailabilities of two extended-release lithium carbonate products and an immediate-release product were compared. Nonsmoking healthy volunteers ages 20-31 (n = 12) were randomly assigned to one of three groups and given three treatments, each separated by a one-week period. The treatments, which were given to each group in a different sequence, consisted of three 300-mg immediate-release lithium carbonate tablets (Lithotab), two 450-mg extended-release lithium carbonate tablets (Eskalith CR), and three 300-mg extended-release lithium carbonate tablets (Lithobid). Blood samples were collected just before drug administration and at intervals up to 48 hours afterward. Urine was collected for 96 hours. Plasma and urine lithium concentrations were determined by flame-emission spectrophotometry, and lithium pharmacokinetic values and the cumulative urinary excretion of lithium were computed. Mean maximum plasma lithium concentration (Cmax) differed significantly among all three lithium carbonate products. Eskalith CR produced a 40% lower Cmax and Lithobid a 25% lower Cmax than Lithotab; Lithobid produced a 23% higher Cmax than Eskalith CR. Lithotab had a significantly shorter mean time to maximum plasma lithium concentration than either extended-release product. Mean cumulative urinary excretion of lithium did not differ significantly among the three products. Two extended-release lithium carbonate products were not bioequivalent when given in single doses to healthy volunteers.