Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1 Pindolol is a non-selective beta-adrenoceptor blocking agent; its affinity to adrenoceptors in guinea pig atria (beta 1) is not significantly different from that in guinea pig trachea (beta 1 + beta 2) and canine vascular smooth muscle (beta 2). 2 Pindolol displays a striking diversity of agonist activities in isolated tissues. Stimulant effects correspond to 40--50% of the maximum effects of isoprenaline in isolated kitten atria and guinea pig trachea and to only 10% in guinea pig atria. Effects in canine isolated mesenteric vessels are those of a full agonist, maximum responses equaling those of isoprenaline. These findings suggest that the stimulant effects of pindolol are exerted principally on beta 2-adrenoceptors. 3 Cardiac stimulation produced by pindolol in the dog is sufficient to compensate for the cardiac depression resulting from blockade of beta-adrenoceptors in the heart. Reductions in cardiac output and compensatory increases in total peripheral resistance do not occur or are much smaller than those produced by beta-adrenoceptor blocking agents lacking sympathomimetic activity. 4 Pindolol-induced relaxation of bronchial smooth muscle prevents or minimizes the bronchoconstrictor effects of injected spasmogens in the cat. 5 Pindolol has marked vasodilator activity, small doses reducing femoral and mesenteric vascular resistance by approximately 30%. Doses comparable to those used in hypertensive patients lower blood pressure by 20 mmHg in non-anaesthetized dogs.
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PMID:Pindolol--the pharmacology of a partial agonist. 704 8

Regional myocardial function was assessed by multidirectional echocardiography from eight standardized segments around the left ventricle. Thirty-six subjects (healthy, severe angina pectoris, or acute myocardial infarction) were studied 15 minutes either after the beta 1-selective beta-blocking drug metoprolol had been administered in total doses of 2 and 10 mg intravenously or after pindolol, a beta blocker with intrinsic sympathomimetic activity (ISA), in total doses of 0.2 and 1.0 mg intravenously had been given. Metoprolol and pindolol reduced rate-pressure product (p less than 0.001 each), heart rate (p less than 0.001), and systolic blood pressure (p less than 0.05 to 0.001) in almost the same way. In patients with acute myocardial infarction, 0.2 mg pindolol improved ST segments by 33% and 2 mg metoprolol by 18%. Left ventricular diameter increased (p less than 0.001) and ejection fraction decreased (p less than 0.05) after metoprolol but not after pindolol. Pindolol did not reduce wall motion amplitudes of healthy myocardial segments, while metoprolol did ( p less than 0.01). The overall contractile function of the left ventricle is characterized by composite segmental amplitudes from both ischemic and healthy ventricular regions. In ischemic hearts this function remained unchanged after metoprolol but improved markedly after pindolol (p less than 0.005). Thus, while intravenous pindolol and metoprolol produced equal reductions in rate-pressure product, pindolol, a beta-adrenergic-blocking drug with intrinsic sympathomimetic activity, evoked less cardiac depression and thus provided a cardiac safety factor not afforded by the beta- 1-selective metoprolol.
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PMID:Cardiac safety of acute beta blockade: intrinsic sympathomimetic activity is superior to beta-1 selectivity. 710 33

Nurse practitioners who are responsible for the clinical management of patients with hypertension must choose antihypertensive medications that minimize side effects. Nurse practitioners must be aware of the drugs' potential influences on physiologic and psychological variables and include adequate assessment of these responses in patients during treatment. Pindolol, propranolol, and hydrochlorothiazide were equally effective in reducing systolic and diastolic blood pressure in essential hypertensives, although pindolol and hydrochlorothiazide did not affect resting heart rate (an advantage in some patients). Hydrochlorothiazide was associated with a trend for several negative mood changes in black subjects; depression scores of black subjects were significantly increased with hydrochlorothiazide. The results of this study indicate the need to consider race and other factors in research about antihypertensive mood responses.
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PMID:Blood pressure and mood responses in hypertensive patients on antihypertensive medications. 824 Aug 80

Spontaneous neuronal activity in the solitary tract nucleus was recorded extracellularly in a brain slice preparation during bath-application of 5-HT1 and 5-HT2 receptor-selective agonists and antagonists. The 5-HT1A/5-HT1B agonist 5-carboxamidotryptamine depressed activity in 20 of 25 neurons studied. The remaining five neurons were unaffected. The 5-HT1A/5-HT1B antagonist pindolol prevented the 5-carboxamidotryptamine-induced changes, whereas the 5-HT1A antagonist spiroxatrine and the 5-HT2 antagonists ketanserin and mianserin were ineffective. Application of the 5-HT1/5-HT2 agonist alpha-methylserotonin depressed activity in 16 of 19 neurons, whereas the remaining three neurons were unresponsive. Pindolol blocked alpha-methylserotonin-induced changes of activity, but spiroxatrine, ketanserin and mianserin were ineffective. Finally, the 5-HT2 agonist DOI was applied to seven neurons. Six were unresponsive to DOI, and one responded with a depression of activity. These data provide electrophysiological evidence for the presence of 5-HT1 receptors in the nTS, presumably of the 5-HT1B subclass, but cast further doubt on the contribution of 5-HT2 and 5-HT1A receptors to the actions of serotonin in the nucleus.
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PMID:Effects of serotonin-1 and serotonin-2 receptor agonists on neuronal activity in the nucleus tractus solitarius. 878 74

Pindolol, a beta-adrenergic and presynaptic 5-HT1 vA antagonist, when added to specific serotonin reuptake inhibitors, potentiates the antidepressant action, leading to an earlier onset of effect. Following on from the suggestion that nefazodone, a specific serotonin reuptake inhibitor and antagonist of 5-HT2, improves 5-HT1A-mediated transmission, we used a pindolol and nefazodone combination treatment for major depressive disorder. Twenty outpatients underwent a 4-week trial. Patients were seen twice a week, and completed efficacy and safety measures including the 17-item Hamilton Depression Scale, the Montgomery-Asberg Depression Rating Scale and the Clinical Global Impression scales. Results demonstrated significant improvement in all efficacy measures after one visit (2-4 days of treatment), with decreasing depression scores on all measures continuing throughout the trial. After 1 week of treatment, 15 out of 20 patients had experienced a 50% or greater reduction in their 17-item Hamilton Depression Scale scores. Remission rates were dramatic, with 40% of patients in remission after 1 week of treatment and 90% after 4 weeks. This open study of nefazodone-pindolol combination therapy suggests that this may be a new treatment option for patients with major depressive disorder; however, it needs to be replicated in a double-blind trial before conclusions regarding efficacy and safety can be made.
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PMID:Fast onset: an open study of the treatment of major depressive disorder with nefazodone and pindolol combination therapy. 921 44

1. It has been hypothesized that 5-HT1A autoreceptor antagonists may enhance the therapeutic efficacy of SSRIs and other antidepressants. Although early clinical trials with the beta-adrenoceptor/5-HT1 ligand, pindolol, were promising, the results of recent more extensive trials have been contradictory. Here we investigated the actions of pindolol at the 5-HT1A autoreceptor by measuring its effect on 5-HT neuronal activity and release in the anaesthetized rat. 2. Pindolol inhibited the electrical activity of 5-HT neurones in the dorsal raphe nucleus (DRN). This effect was observed in the majority of neurones tested (10/16), was dose-related (0.2-1.0 mg kg(-1), i.v.), and was reversed by the 5-HT1A receptor antagonist, WAY 100635 (0.1 mg kg(-1), i.v.), in 6/7 cases tested. 3. Pindolol also inhibited 5-HT neuronal activity when applied microiontophoretically into the DRN in 9/10 neurones tested. This effect of pindolol was current-dependent and blocked by co-application of WAY 100635 (3/3 neurones tested). 4. In microdialysis experiments. pindolol caused a dose-related (0.8 and 4 mg kg(-1), i.v.) fall in 5-HT levels in dialysates from the frontal cortex (under conditions where the perfusion medium contained 1 microM citalopram). In rats pretreated with WAY 100635 (0.1 mg kg(-1), i.v.), pindolol (4 mg kg(-1), i.v.) did not decrease, but rather increased 5-HT levels. 5. We conclude that, under the experimental conditions used in this study, pindolol displays agonist effects at the 5-HT1A autoreceptor. These data are relevant to previous and ongoing clinical trials of pindolol in depression which are based on the rationale that the drug is an effective 5-HT1A autoreceptor antagonist.
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PMID:Electrophysiological and neurochemical evidence that pindolol has agonist properties at the 5-HT1A autoreceptor in vivo. 963 Mar 61

The realisation that pindolol may accelerate the effects of some antidepressant drugs in clinical trials has added extra impetus to the search for faster acting antidepressants. Currently, no animal model of depression can identify potential faster acting antidepressant drugs or drug combinations. In this study, we investigate the effects of combining pindolol (2 mg/kg, s.c., bid) with the antidepressant paroxetine (2.5 mg/kg, i.p., bid) in the olfactory bulbectomised rat, an animal model of chronic (but not acute) antidepressant activity. Ambulation scores were measured in separate groups of rats, following 3, 7 and 14 days of treatment. Further, we simultaneously study adaptive changes in 5-HT1A receptor function, utilising alterations in the hypothermic response to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Pindolol in combination with paroxetine attenuated the hypothermic effects of 8-OH-DPAT as early as 3 days with a full reversal evident following 7 days, whereas paroxetine alone did so after 14 days only. Likewise, paroxetine alone reversed the olfactory bulbectomy-induced hyperactivity in the open field following 14 days of treatment only, this being the normal time of an 'antidepressant' response in this model. However, the group treated with both paroxetine and pindolol failed to reverse the hyperactive response. This suggests that a factor intrinsic to pindolol antagonises the behavioural effects of paroxetine in the olfactory bulbectomised rat. It also demonstrates that the reversal of this aspect of the olfactory bulbectomy-induced behavioural syndrome is insensitive to the potential faster onset of antidepressant action induced by pindolol. The ability of the combination group to attenuate the hypothermic effects of 8-OH-DPAT much faster further emphasises the role of the 5-HT1A receptor in the mechanism of action of antidepressants and as a target for the development of faster acting antidepressants. However, an animal model sensitive to the effects of any such compound and the actions of pindolol remains elusive.
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PMID:Combining pindolol and paroxetine in an animal model of chronic antidepressant action--can early onset of action be detected? 971 63

Depression is a widespread, recurrent disease that sometimes remains inadequately managed by current drug therapy. There is a need to develop better antidepressants that ideally would have a more rapid onset of action, a higher response rate, and improved long-term efficacy. The latest generation of antidepressants have novel dual modes of action, and the results of recent clinical trials indicate that they may have superior efficacy to established drug therapies such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Dual acting drugs, such as venlafaxine, a serotonin-norepinephrine reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, have been shown to have a rapid onset of action. The long-term efficacy of mirtazapine and of venlafaxine was also found to be superior to that of TCAs. Pindolol was found to accelerate response to SSRI therapy. However, these results were dependent on the patient population. These studies clearly suggest that the latest generation of antidepressants offer a more rapid response to treatment, an improved response rate, and superior long-term efficacy than conventional therapy. The clinical importance of these results should not be overlooked.
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PMID:New developments in the treatment of depression. 1040 20

Serotonin(1A) (5-HT(1A)) receptors have been implicated in the pathophysiology and treatment of anxiety and depression and are a target for novel drug development. In this qualitative study, positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635 were used to assess 5-HT(1A) autoreceptor and postsynaptic receptor occupancy in man in vivo by five different compounds with nanomolar affinity for this site. Occupancy by pindolol, penbutolol, buspirone, EMD 68843, and S 15535 was compared to test-retest data from 10 healthy volunteers. All drugs, apart from buspirone, displayed occupancy at the 5-HT(1A) receptor site. Pindolol demonstrated a preferential occupancy at the autoreceptor compared to the postsynaptic receptor over a plasma range of about 10-20 ng/mL. Differential occupancy may be an important component of novel drug action. The level of autoreceptor or postsynaptic occupancy needed to achieve significant physiological effects is not known, although it is of note that none of the drugs in this study achieved occupancies beyond 60%. Overall this study demonstrates the utility of PET in aiding novel drug development.
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PMID:Drug action at the 5-HT(1A) receptor in vivo: autoreceptor and postsynaptic receptor occupancy examined with PET and [carbonyl-(11)C]WAY-100635. 1096 59

Positron-emission tomography (PET) provides potential in neuropsychiatric drug development by expanding knowledge of drug action in the living human brain and reducing time consumption and costs. The 5-hydroxytryptamine(1A) (5-HT(1A)) receptor is of central interest as a target for the treatment of anxiety, depression, and schizophrenia. Research on the clinical significance of the 5-HT(1A) receptor now benefits from the highly selective radioligand [carbonyl-(11)C]WAY-100635 (WAY) for quantitative determination of 5-HT(1A) receptors in the primate and human brain in vivo using PET. In this paper, three studies are reviewed to demonstrate the suitability of WAY as radioligand for quantification of central 5-HT(1A) receptors in brain and as an applicable tool for drug development. In the first study a monkey model was used to characterize WAY binding. It was confirmed that the reference ligand 8-OH-DPAT and psychoactive drugs such as buspirone and pindolol occupies 5-HT(1A) receptors in the primate brain. Pindolol is an beta-adrenoreceptor antagonist with a high affinity to 5-HT(1A) receptors. This drug has been suggested in combination with selective serotonin reuptake inhibitors for the treatment of depression and was given to healthy males in the second study. Pindolol induced a marked inhibition of central 5-HT(1A) receptors as calculated by the ratio-analysis method and simplified reference tissue model, 2 h after administration of 10 mg as a single oral dose. This observation suggests that pindolol may have a role for the suggested potentiation of selective serotonin reuptake inhibitor treatment of depression. The third study was on robalzotan (NAD-299), a recently developed 5-HT(1A) receptor antagonist and putative drug with implications for the treatment of depression. In the cynomolgus monkey brain, robalzotan in the dose range 2-100 microg/kg IV occupied 5-HT(1A) receptors in a dose-dependent and saturable manner with a maximal calculated occupancy of 70-80%. The relationship between robalzotan plasma concentration and 5-HT(1A) receptor occupancy could be described by a hyperbolic function that was used to guide the selection of appropriate doses in man. In a subsequent PET study of robalzotan binding to 5-HT(1A) receptors in the living human brain, similar results have been replicated recently. These studies reviewed here illustrate and corroborate that quantitative neuroimaging of receptor binding has potential for the evaluation and dose finding of new central nervous system drugs.
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PMID:Use of PET and the radioligand [carbonyl-(11)C]WAY-100635 in psychotropic drug development. 1096 60


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