Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial.

OBJECTIVE: To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression. METHOD: After a 7- to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine (20-40 mg), imipramine (gradual upward titration to 200-300 mg), or placebo. The two primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [HAM-D] score < or = 8 or > or = 50% reduction in baseline HAM-D) and change from baseline HAM-D score. Other depression-related variables were (1) HAM-D depressed mood item; (2) depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (K-SADS-L); (3) Clinical Global Impression (CGI) improvement scores of 1 or 2; (4) nine-item depression subscale of K-SADS-L; and (5) mean CGI improvement scores. RESULTS: Paroxetine demonstrated significantly greater improvement compared with placebo in HAM-D total score < or = 8, HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of 1 or 2. The response to imipramine was not significantly different from placebo for any measure. Neither paroxetine nor imipramine differed significantly from placebo on parent- or self-rating measures. Withdrawal rates for adverse effects were 9.7% and 6.9% for paroxetine and placebo, respectively. Of 31.5% of subjects stopping imipramine therapy because of adverse effects, nearly one third did so because of adverse cardiovascular effects. CONCLUSIONS: Paroxetine is generally well tolerated and effective for major depression in adolescents.

Paroxetine in the treatment of generalized anxiety disorder: results of a placebo-controlled, flexible-dosage trial.

BACKGROUND: The objective of this randomized, double-blind, placebo-controlled study was to investigate the efficacy and safety of paroxetine in outpatients with generalized anxiety disorder (GAD). METHOD: Male and female outpatients 18 years and older who met DSM-IV criteria for GAD and had baseline scores of at least 20 on the Hamilton Rating Scale for Anxiety (HAM-A) were randomly assigned to treatment with paroxetine (20-50 mg/day) or placebo for 8 weeks. The primary efficacy variable was the mean change from baseline in the total score of the HAM-A. Additional key efficacy variables were the change from baseline in the scores of the HAM-A items anxious mood and tension, the anxiety subscale of the Hospital Anxiety and Depression Scale, and the Sheehan Disability Scale (SDS). The proportions of patients fulfilling response and remission criteria at week 8 were also determined. RESULTS: The intent-to-treat population included 324 patients. At week 8, compared with the placebo group (N = 163), the paroxetine group (N = 161) had a significantly greater reduction of GAD symptoms on all of the above-mentioned efficacy variables. On the HAM-A anxious mood item, which encompasses the cardinal symptoms of GAD, significantly greater efficacy was observed from week 1 and on the SDS significantly greater improvement was documented in the domain "social life" as early as week 4 for paroxetine compared with placebo. In both the last-observation-carried-forward and completer data sets, significantly greater proportions of paroxetine-treated patients achieved response or remission by week 8. Treatment with paroxetine was well tolerated, and the number and type of adverse events recorded in the paroxetine group correspond to the known safety profile of this medication. CONCLUSION: Paroxetine in doses of 20 to 50 mg once daily is effective in the treatment of patients with GAD. Improvement of core symptoms of GAD occurs early and is associated with significant reduction in disability after only 8 weeks of treatment.

A double-blind placebo-controlled study of auranofin in patients with psoriatic arthritis.

Two hundred thirty-eight patients with psoriatic arthritis were entered into a 6-month, multicenter, double-blind trial comparing auranofin and placebo. Polyarthritis (greater than 5 tender joints) was present in 90% of the patients, and 94% were seronegative. Auranofin treatment was statistically superior to placebo treatment, according to physician's global assessment and functional scores. A trend in favor of auranofin treatment was seen for each of the other disease parameters studied. Psoriasis worsened in 6 auranofin-treated patients and in 3 placebo-treated patients. The incidence and nature of other side effects were similar to those observed in similar trials of patients with rheumatoid arthritis. Our observations suggest that the use of auranofin in the treatment of psoriatic arthritis is safe, although its therapeutic advantage over treatment with nonsteroidal antiinflammatory drugs alone is modest.

SK&F 89124, a potent and selective agonist at prejunctional dopamine receptors.

SK&F 89124 (4-[2-(N,N-di-n-propylamino)ethyl]-7-hydroxy-2(3H) indolone) can be considered as a derivative of N,N-di-n-propyldopamine (DPDA) in which the meta-hydroxyl is replaced by a cyclic amide function. SK&F 89124 is at least one order of magnitude more potent than DPDA as an agonist at peripheral inhibitory prejunctional dopamine receptors (DA2 receptors) in the isolated perfused rabbit ear artery. A potent agonist action of SK&F 89124 at the DA2 receptor can also be demonstrated by inhibition of radioactive overflow from prelabelled canine coronary artery or saphenous vein, and in the anesthetized dog as an inhibition of the tachycardia induced by cardioaccelerator nerve stimulation or the increase in hind-limb perfusion pressure induced by stimulation of the lumbar sympathetic chain. SK&F 89124 is a potent inhibitor of the binding of [3H]spiroperidol to D2 receptors in bovine pituitary homogenates. High concentrations of SK&F 89124 do not activate the adenylate cyclase D1 receptor in rat caudate homogenates, nor produce activation of alpha 2-adrenoceptors or H2-histamine receptors in the guinea pig atrium. Although some alpha 1-adrenoceptor mediated vasoconstriction is produced in the rabbit ear artery and rabbit aorta, the concentrations required are several orders of magnitude higher than those active at the DA2 receptor. From these data it is evident that this structural modification can increase both the potency and selectivity of DPDA as a DA2 receptor agonist. The potency and selectivity of SK&F 89124 make this agent a useful tool for determination of the functional role of the DA2 receptor.

Incidence and management of diarrhea during longterm auranofin therapy.

The incidence, severity, and management of diarrhea during longterm administration of auranofin (AF)--up to 33 months--were evaluated prospectively in 137 patients with active rheumatoid arthritis. At least 1 episode of diarrhea was reported in 101 patients (74%), but the rate of occurrence/patient-months of therapy was 24% (569 events/2,370 patient-months of treatment). The monthly prevalence declined from a range of 30-40% during the initial 6 months to about 10% for patients treated for 18-24 months. Most diarrhea was intermittent and mild; only 11 patients (8%) discontinued treatment because of diarrheal symptoms. No intervention was required in 46 of the 101 patients affected. In 44 others, loose stools were successfully managed with antidiarrheal medications, a reduction in dosage, or both. Although diarrhea is a common event during AF administration, particularly early in therapy, for most patients it usually does not significantly interfere with treatment.

Characterization of the antihypertensive activity of SK&F 86466, a selective alpha-2 antagonist, in the rat.

The effects of SK&F 86466 (6-chloro-N-methyl-2,3,4,5-tetrahydro-1-H-3-benzazepine), a potent and selective alpha-2 adrenoceptor antagonist, on blood pressure and heart rate were examined in normotensive and hypertensive rats. SK&F 86466 was approximately 10-fold more potent in lowering blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive than in normotensive rats, when administered by i.v. infusion. A dose-related antihypertensive effect was observed in conscious DOCA-salt rats after p.o. doses of SK&F 86466 (2-15 mg/kg), with a duration of over 6 hr after the highest dose. Oral administration of SK&F 86466 was associated with tachycardia, which reached maximal levels within 15 min after dosing, followed by an interval of bradycardia. The duration of antihypertensive activity observed with SK&F 86466 was at least 6 hr, compared to less than 90 min with phentolamine, at doses which produced equal peak reductions in blood pressure in conscious DOCA-salt rats. In contrast, heart rate was still significantly elevated by phentolamine 90 min postdosing, whereas the transient tachycardia induced by SK&F 86466 had dissipated within 30 min. SK&F 86466 was also an effective antihypertensive agent in the spontaneously hypertensive rat, although lower antihypertensive efficacy was observed than in the DOCA-salt model. SK&F 86466 was even less effective in the two-kidney one-clip Goldblatt model in which hypertension is maintained by the renin-angiotensin system rather than by the sympathetic nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular activity of SK&F 64139 in the hypertensive rat.

SK&F 64139 (7,8-dichloro-1,2,3,4-tetrahydroisoquinoline) produces a dose-related antihypertensive effect in rats treated with desoxycorticosterone acetate and administered saline in their drinking water (DOCA-salt rats), lowering both systolic and diastolic blood pressure by 40 mm Hg after an oral dose of 25 mg/kg in a conscious animal. This antihypertensive effect can also be observed after intravenous infusion in an anesthetized DOCA rat. The fall in blood pressure is accompanied by bradycardia, which can be blocked by the combination of propranolol plus vagotomy, and a decrease in peripheral vascular resistance. In contrast to the results in the DOCA rat, only minimal effects on blood pressure were produced in normotensive rats. Although SK&F 64139 is a potent inhibitor of phenylethanolamine N-methyltransferase (PNMT), the time course of blood pressure reduction is not consistent with PNMT inhibition as a mechanism for its antihypertensive action. SK&F 64139 decreases the turnover rate of cardiac norepinephrine in DOCA-salt rats, suggesting that its antihypertensive effect may results from a centrally mediated inhibition of sympathetic outflow to the periphery.

1,3-Diaryltriazenes: a new class of anorectic agents.

A series of substituted 1,3-diaryltriazenes has been synthesized and tested for anorectic activity. Several members of the series were effective; one compound, 1,3-bis[2-cyano-5-(trifluoromethyl)phenyl]triazene, was particularly active, causing weight loss in rats, dogs, and squirrel monkeys. It was devoid of overt central nervous system activity, and compared to previously reported biologically active triazenes, it was relatively nontoxic up to 30 days of drug administration.

Potential usefulness of renal vasodilators in hypertension and renal disease: SK&F 82526.

SK&F 82526 and its enantiomers have been shown to increase renal blood flow and decrease renal vascular resistance in the anesthetized dog. The effect of the racemate on lowering systemic blood pressure in the anesthetized dog and the spontaneously hypertensive rat has been shown to be caused by the R-enantiomer with the S-enantiomer being devoid of significant activity on blood pressure. The mechanism by which the R-enantiomer decreases blood pressure is not systemic vasodilatation or prejunctional inhibition of norepinephrine release but appears to result from a unique stimulation of the postjunctional dopamine receptor. Racemic SK&F 82526 also has been shown to increase renal blood flow in an ischemic model of acute renal failure.

Studies on the mechanisms involved in the cardiovascular response of the rat to hemorrhage.

Acute reductions in blood volume and in arterial pressure produced by hemorrhage in the rat resulted in significant changes in heart rate. In general, when bleeding lowered mean arterial blood pressure to 90 mmHg or less, heart rate fell in proportion to the depth of hypotension, but when arterial pressure remained above 100 mmHg, regardless of the volume of shed blood, heart rate increased. The bradycardia observed when the animals were bled to low pressures (40 mmHg) could be prevented by vagotomy or with a combination of atropine and propranolol. This suggests the effect is reflex action centrally mediated. Propranolol alone had only small effects on the heart rate response, indicating that the reflex is predominantly under vagal influence. Phenoxybenzamine or adrenal demedullation had no effect on heart rate or blood pressure changes during or after hemorrhage. Pargyline, at a dose which significantly inhibited MAO and increased brain stem norepinephrine and dopamine levels, reduced the magnitude of the shock bradycardia. These results are discussed in relation to our earlier report (Pendleton et al., 1980a) which indicates that the potent inhibitor of epinephrine synthesis, SK & F 64139, will prolong the bradycardia and hypotension associated with hemorrhage in this model.

Mechanism for gastric antisecretory effects of desmethylimipramine in rats.

The mechanism for the gastric antisecretory action of desmethylimipramine (DMI) was studied using the pylorus-ligated rat preparation. DMI was approximately 40 times more potent in decreasing gastric acid secretion when given into the lateral ventricles of the brain than when administered intravenously. The antisecretory effects of DMI could be blocked by the alpha 2-adrenoceptor antagonists yohimbine and SK&F 72223 and mimicked by central administration of an alpha 2-agonist. It could not be blocked by the alpha 1-antagonist prazosin or mimicked by alpha 1-adrenoceptor agonists. SK&F 72223 and yohimbine themselves produced small increases in gastric acid, but the increase output by SK&F 72223 failed to reduce the antisecretory response to atropine. Since DMI is not an alpha 2-adrenoceptor agonist, but is a potent inhibitor of norepinephrine uptake, these data suggest that the effects of DMI on gastric acid secretion are mediated indirectly via inhibition of catecholamine uptake at central synapses containing alpha 2-adrenoceptors.

The effects of PNMT inhibitors upon cardiovascular changes induced by hemorrhage in the rat.

Rapid bleeding in normotensive Sprague-Dawley rats produces a marked fall in arterial blood pressure and a profound decrease in heart rate. The bradycardia, which is abolished by vagotomy and partially antagonized by atropine, was significantly prolonged by pretreatment with SK&F 64139, a potent in vivo inhibitor of peripheral and central (CNS) phenylethanolamine N-methyltransferase (PNMT). This effect of the drug was accompanied by a prolonged hypotensive period and was not seen with SK&F 29661, a selective inhibitor of peripheral (adrenal) PNMT or with SK&F 72223, a structural analog of SK&F 64139 which has no effect on PNMT. These data suggest that the effects of SK&F 64139 are a result of inhibition of central PNMT and that epinephrine may function as a central neurotransmitter mediating cardiovascular responses to hemorrhage, at least under the conditions of these studies.