Effects Of Pindolol Research Articles

A short-term double-blind randomized controlled pilot trial with active or placebo pindolol in patients treated with venlafaxine for major depression

Background: Pindolol has been widely investigated as an augmenter of antidepressant drug response. Results have been inconsistent. In this study, we used pindolol together with venlafaxine because of its ability to achieve a rapid onset of serotonin transporter blockade. Aims: The object of this study was thus to investigate if pindolol augments the antidepressant response to venlafaxine. Methods: Patients with major depression were randomized to either active or placebo pindolol 20 mg retard daily dosage and concomitantly treated with venlafaxine for 19 days. Depression severity was evaluated at four visits. Plasma concentrations of venlafaxine and its major metabolites O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) and pindolol were analysed. The ratio of ODV/venlafaxine was calculated. A low ratio corresponds to patients being poor metabolizers and a high ratio corresponds to patients being extensive metabolizers. Results: No statistically significant difference in depression outcome was found between treatment groups. A statistically significant effect was, however, found of the ratio of ODV/venlafaxine on depression outcome, showing an augmenting effect of pindolol in patients with a low ratio, and the reverse in patients with a high ratio. Conclusion: The differential effect of pindolol, on depression outcome, in patients with varying degrees of venlafaxine metabolism into ODV, corresponds to patients being poor or extensive metabolizers of venlafaxine. From this finding, we conclude that only patients who are poor metabolizers of venlafaxine might benefit from pindolol augmentation. This mechanism might explain some of the variability of outcome in pindolol augmentation studies.

A27-6 Long-term treatment effect of pindolol on neurocardiogenic syncopal syndrome

A27-6 Long-term treatment effect of pindolol on neurocardiogenic syncopal syndrome

A27-6 Long-term treatment effect of pindolol on neurocardiogenic syncopal syndrome

A27-6 Long-term treatment effect of pindolol on neurocardiogenic syncopal syndrome

Evidence of melatonin involvement in pindolol-induced suppression of REM sleep.

The effects of pindolol, melatonin, and the melatonin receptor agonist agomelatine were studied in rats implanted for chronic sleep procedures. Administration of pindolol (1.0-4.0 mg/kg) during the light phase induced a significant reduction of rapid-eye-movement sleep (REMS) and an increase of waking (W). In the rats recorded after receiving 1.0-6.0 mg/kg melatonin no significant differences were found in sleep or W compared with controls. Agomelatine (1.0-6.0 mg/kg) induced a significant increase of light sleep during the first 3 h of the recording period. Pretreatment with melatonin partly prevented the pindolol-induced suppression of REMS. However, agomelatine was ineffective in this respect. Overall, these data suggest that the decreased production of melatonin could play a role in REMS suppression related to pindolol administration.

Pindolol increases extracellular 5-HT while inhibiting serotonergic neuronal activity

The effects of pindolol, a beta-adrenoceptor blocker/putative 5-hydroxytryptamine (5-HT) 1A/1B antagonist, on both the single-unit activity of serotonergic neurons in the dorsal raphe nucleus (DRN) and extracellular 5-HT levels in the caudate nucleus, were examined in freely moving cats. Administration of (±)-pindolol (1 and 10 mg/kg, s.c.) decreased neuronal activity and increased 5-HT levels in a dose- and time-dependent manner. The subsequent administration of WAY-100635 { N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridinyl)cyclohexanecarboxamide} (0.2 mg/kg, s.c.), a selective 5-HT 1A receptor antagonist, blocked pindolol-induced neuronal suppression and potentiated 5-HT output. These results indicate that pindolol may be acting at the level of the nerve terminal to increase 5-HT.

Electrophysiological and neurochemical evidence that pindolol has agonist properties at the 5-HT1A autoreceptor in vivo.

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.

P.1.041 Effect of pindolol in hastening response to serotoninergic antidepressants: An open study in severely depressed female in-patients

P.1.041 Effect of pindolol in hastening response to serotoninergic antidepressants: An open study in severely depressed female in-patients

Effect of pindolol on the function of pre- and postsynaptic 5-HT1A receptors: In vivo microdialysis and electrophysiological studies in the rat brain

In microdialysis studies, somatodendritic 5-HT1A receptors in the dorsal raphe nucleus (DRN) were activated by the local infusion of 50 microM citalopram, a selective 5-HT reuptake inhibitor (SSRI). This reduced extracellular 5-HT by about 50% in dorsal striatum, an area receiving 5-HT afferents exclusively from the DRN. (-)Pindolol dose-dependently attenuated this citalopram-induced reduction of striatal extracellular 5-HT. Consistent with its 5-HT reuptake blocking properties, single doses of the SSRI paroxetine (1 and 3 mg/kg IP) and citalopram (1 mg/kg IP) significantly elevated extracellular 5-HT in the dorsal striatum. Pretreatment with (-)pindolol (15 mg/kg IP) potentiated the effect of 3 mg/kg paroxetine and 1 mg/kg citalopram on striatal extracellular 5-HT. A 2-day treatment with 10 mg/kg/day (SC) of paroxetine reduced by 60% the spontaneous activity of 5-HT neurons of the DRN. However, 5-HT neurons displayed normal activity in rats treated with paroxetine and (-)pindolol for 2 days. The inhibitory effect of LSD on 5-HT neuronal firing activity was also markedly attenuated in (-)pindolol-treated rats, indicating that somatodendritic 5-HT1A receptors were blocked by (-)pindolol. To determine whether (-)pindolol also blocked postsynaptic 5-HT1A receptors in hippocampus, 5-HT and the prototypical 5-HT1A agonist 8-OH-DPAT were applied by microiontophoresis onto CA3 pyramidal neurons following the same treatment. (-)Pindolol did not modify the responsiveness of these neurons to 5-HT and 8-OH-DPAT. Taken together, these results indicate that (-)pindolol can potentiate the effects of an SSRI on extracellular 5-HT concentration by preventing the activation of somatodendritic 5-HT1A autoreceptors resulting from the blockade of the 5-HT transporter in the raphe. This presumably leads to enhanced 5-HT neurotransmission because (-)pindolol would not alter the responsiveness of certain postsynaptic 5-HT1A receptors, such as those located on hippocampal CA3 pyramidal neurons. These results provide a neurobiological basis for the reported potentiation of certain antidepressant drugs by pindolol in major depression.

Modification of the discriminative stimulus effects of 8-OH-DPAT, buspirone and the ??-adrenoreceptor antagonist pindolol after chronic administration of the 5-HT agonist 8-OH-DPAT in the pigeon

The involvement of adrenoreceptor blocking drugs with the 5-HT(1A)-mediated discriminative stimulus was studied in pigeons trained to discriminate the 5-HT(1A) receptor agonist 8-OH-DPAT (0.3mg/kg) from saline. Cumulative dose-response curves were determined for 8-OH-DPAT, the beta-adrenergic antagonist pindolol, the alpha(1)-antagonist prazosin, as well as for the 5-HT(1A) agonist buspirone, before, during and after (8-OH-DPAT and pindolol) chronic administration of 8-OH-DPAT (3.0mg/kg/day for 6 weeks). The dose-response curves for 8-OH-DPAT and buspirone, which substituted for 8-OH-DPAT, were shifted to the left during chronic 8-OH-DPAT administration. Prazosin did not substitute for 8-OH-DPAT at any time throughout the course of the study. Pindolol did not substitute for 8-OH-DPAT before chronic administration, but did so during and after 8-OH-DPAT was administered chronically. Chronic administration of 8-OH-DPAT resulted in a heightened sensitivity not only to the 5-HT(1A) agonists 8-OH-DPAT and buspirone, but also to what appear to be partial agonist effects of pindolol. This approach represents a first step in the in vivo characterization of changes in 5-HT(1A) sensitivity after chronic administration of 8-OH-DPAT using the drug discrimination procedure. This method may provide a useful behavioral model with which to investigate the mechanisms of anxiolytic and antidepressant effects of 5-HT(1A) agonists and beta-adrenoceptor blocking drugs that only become apparent after 2 to 4 weeks of chronic administration.

The effect of pindolol on creatine kinase is not due to beta 2‐ adrenoceptor partial agonist activity [letter; comment

We read with interest the recent article (Tomlinson et al., 1990) which demonstrated that an increase in serum creatine kinase (CK) activity occurs during treatment with the β-adrenoceptor blocking drug pindolol. As a possible explanation for this phenomenon the authors postulated that the β 2 -adrenoceptor partial agonist activity (PAA) of pindolol on skeletal muscle was responsible for this effect. Known effects of β 2 -receptor stimulation on skeletal muscle include finger tremor and hypokalaemia. However, the effect of β 2 -adrenoceptor stimulation on creatine kinase has not to our knowledge been previously reported in the literature. We therefore investigated the effects of inhaled terbutaline (a known selective β 2 -adrenoceptor agonist) on serum creatine kinase activity in 34 normal volunteers (mean ± s.e. mean age, 25 ± 3 years)

Compared with atenotol, pindolol decreased bradycardia, tiredness, and cold extremities in hypertension, but increased transient sleep disturbance

Source Citation Abrahamsen AM, Digranes 0, Gisholt K. Comparison of the side effects of pindolol and atenolol in the treatment of hypertension. J Intern Med. 1990;228:219-22. 2205704

Pindolol decreases prolactin and growth hormone responses to intravenousL-tryptophan

The effects of pindolol on the prolactin (PRL) and growth hormone (GH) responses to intravenous tryptophan (LTP) were studied in eight healthy male volunteers. Pindolol pretreatment (40 mg over 48 h) markedly attenuated the GH response to LTP and modestly, but significantly, reduced the LTP-induced increase in plasma PRL. The disposition of LTP following infusion was not altered by pindolol. While the data are consistent with 5-HT1A receptor mediation of PRL and GH responses to LTP, the intrinsic sympathomimetic actions of pindolol might also be involved in the attenuation of the endocrine responses to LTP.

Beta-blockade with intrinsic sympathetic activity modifies favorably exercise-induced changes in plasma lipoproteins

The effects of beta-blockade on acute exercise-induced changes in plasma lipoprotein levels were investigated in 12 healthy normotensive subjects by use of beta-blockers of three types: a nonselective agent, a beta 1-selective agent, and a nonselective agent with intrinsic sympathomimetic activity (ISA) or partial agonist activity. Each subject received each drug and a placebo for 1 wk each according to a randomized double-blind crossover design. After placebo, exercise caused 10-20% increases in total plasma cholesterol and the high-density lipoprotein (HDL)-cholesterol fraction. The total-to-HDL cholesterol ratio fell, particularly during the 30-min recovery phase. Pindolol treatment increased resting values of HDL cholesterol (from 43 +/- 4 to 48 +/- 4 mg/dl) and potentiated the response to exercise (to 59 +/- 5 vs. 51 +/- 4 mg/dl after placebo). The total-to-HDL cholesterol ratio was significantly lower after pindolol treatment than after placebo. In contrast, neither atenolol nor timolol affected exercise-induced changes in plasma lipoprotein levels. The effects of pindolol on other study parameters (exercise endurance and exercise-induced increases in systolic blood pressure, heart rate, and potassium) were similar to the effects of the nonselective agent, timolol. We conclude that the effects of pindolol on the plasma lipid profile are due to its ISA and that the process activated (possibly plasma lecithin-cholesterol acyltransferase activity) is under minimal sympathetic control and, therefore, sensitive to the expression of ISA both at rest and in response to exercise.

Hemodynamic effects of pindolol and atenolol at rest and during isometric exercise: A noninvasive study with healthy volunteers

Hemodynamic effects of intravenous and oral pindolol and atenolol were assessed in ten healthy volunteers by left ventricular echocardiography and systolic time intervals. Measurements were made at rest and during hand-grip-induced isometric exercise. Drug doses were pindolol 0.015 mg/kg intravenously and 10 mg/day orally, atenolol 0.1 mg/kg intravenously, and 50 mg/day orally. Heart rate at rest was reduced by both drugs. The reduction caused by atenolol during oral treatment was significantly greater (p less than 0.01). Intravenously only pindolol reduced mean arterial pressure. During oral treatment atenolol reduced the mean arterial pressure nonsignificantly. Both drugs lowered heart rate during isometric exercise, atenolol being significantly more effective. During oral treatment atenolol blunted the heart-rate reaction to exercise. Mean arterial pressure during isometric exercise rose slightly with both drugs after intravenous administration. During oral treatment only atenolol reduced the mean arterial pressure significantly. Intravenous atenolol reduced cardiac contractility at rest, indicated by significant decreases in fractional shortening, ejection fraction, and the mean velocity of circumferential fiber shortening. In contrast, intravenous pindolol and oral therapy with either drug did not change contractility. Intravenous atenolol raised total peripheral resistance. The preejection period/left ventricular ejection time ratio decreased with intravenous pindolol, while atenolol increased it. In conclusion, atenolol had more negative inotropic and chronotropic effects, especially after acute intravenous administration. Only atenolol reduced cardiac output and increased peripheral resistance. After repeated oral administration, these effects were less apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

２４時間自動血圧計とトレッドミル運動負荷試験による本態性高血圧患者に対するピンドロール徐放剤の効果の検討

２４時間自動血圧計とトレッドミル運動負荷試験による本態性高血圧患者に対するピンドロール徐放剤の効果の検討

Desensitization pattern of cardiac β-adrenoceptor subtypes by prolonged in vivo infusion of pindolol and celiprolol in rats

The regulatory effects of pindolol and celiprolol on cardiac beta-adrenoceptor density were studied in vivo in order to assess the subtype selectivity of their partial agonistic activity (PAA). The substances were continuously administered to rats for 1 week by means of implanted osmotic minipumps. The density of beta-adrenoceptor subtypes were estimated from ICYP saturation binding experiments performed on cardiac ventricular plasma membranes in the presence of a highly selective antagonist (CGP 20172 A or ICI 118,551). Both antagonists were employed at concentrations as high as to block one subtype only without affecting the complementary subtype. For control purposes, rats were also treated with isoprenaline (0.4 mg/kg/h) and propranolol (0.15 mg/kg/h), or vehicle. Pindolol (0.036 mg/kg/h) and celiprolol (0.36 mg/kg/h) reduced the density of ventricular beta 2-adrenoceptors by 46% and 23%, respectively, which--in the case of pindolol--was significant when compared to the non-treated controls. Both compounds, however, produced a small, but distinct increase in the number of beta 1-adrenoceptors by approximately 26%. This finding is in contrast to the propranolol--induced up-regulation of both beta 1- and beta 2-adrenoceptors by approximately 80%. Since supramaximal doses of each drug were administered, a significant smaller increase of beta 1-adrenoceptors by pindolol and celiprolol--as compared to the increase produced by propranolol--can be interpreted as evidence for a PAA of pindolol and celiprolol on beta 1-adrenoceptors as well. Isoprenaline as a full agonist caused a marked loss of of both beta-adrenoceptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of behavioral problems with pindolol

A study was conducted on a group of chronically hospitalized, brain-damaged male patients to assess the effectiveness of treatment with pindolol on behavioral problems. The study was conducted in two parts. The first was a double-blind, placebo-controlled analysis of the effect of pindolol on assaultive behavior, both verbal and physical. The second part was open and sought to determine whether pindolol would diminish such behaviors as resistance to care, sexual preoccupation, or provocation of others, which were sufficient to preclude placement at a lower level of care. These target behaviors and nursing interventions were monitored and clinical global assessments of improvement in behavior and of suitability for lower levels of care were developed. Eight of 13 patients were considered improved. Those with significant premorbid personality disorders showed little benefit. Pindolol appears to ameliorate some management problems and, by inference, improve the quality of life in many patients with behavioral pathology due to organic brain disease.

Effects of pindolol and propranolol on blood lipids in hypertensive patients

Since beta-blockers could affect lipid levels at the therapeutic dose range in hypertensive patients, a parallel 6-month randomized trial with pindolol (PDL) (16 pts.) and propranolol (PPL) (23 pts.) was designed (mean age = 55 + 7.1 years and 57 + 8.0 years; 9 males, 7 females and 15 males, 8 females, respectively). Total cholesterol, LDL and HDL fractions, and triglycerides (TGs) were determined before (washout phase) and during 1, 3, and 6 months of therapy. Patients were instructed to maintain their usual dietary habits. Daily drug doses were adjusted step by step to attain an optimal hypotensive effect (PDL 15-45 mg, PPL 180-240 mg). In the PPL-treated group, total cholesterol and LDL did not change significantly, HDL decreased (from 45.2 to 40.5 mg/dl, p less than 0.05) and TG increased (from 133 to 169 mg/dl, p less than 0.05). In the PDL group total cholesterol and LDL did not change either, but HDL increased (35.9 to 44.7 mg/dl, p less than 0.01) and TGs, were reduced (from 169 to 131 mg/dl, p less than 0.05). No dose-effect relationship was recorded. It is concluded that pindolol does not negatively influence HDL nor the TG blood lipid profile as does PPL. Accordingly, pindolol might be preferred to propranolol in the treatment of hypertensive patients with an unfavorable lipid profile, but this assumption remains to be proven in larger, prospective, long-term followup trials.

Effect of pindolol versus atenolol on lipid profile in hypertensive patients

The effect of pindolol (a beta-blocker with intrinsic sympathomimetic activity, ISA) on fasting plasma lipid profile in 30 hypertensive patients was compared with atenolol (without ISA) in a crossover single blind study. Both drugs lowered blood pressure. HDL-cholesterol increased significantly with pindolol (from 1.15 ± 0.05 to 1.34 ± 0.05 mmoi/1 at 12 weeks, P < 0.001), but not with atenolol. VLDL-cholesterol increased with atenolol (from 0.57 ± 0.09 to 0.86 ± 0.14 mmol/1 at 12 weeks, P < 0.002), while there was no change with pindolol. These changes in lipoprotein profile suggest a more favourable effect of pindolol than of atenolol on lipid profile.

Effect of pindolol on changes in serum lipids induced by hydrochlorthiazide.

Forty-two patients with essential hypertension, WHO I-II, and a diastolic blood pressure greater than or equal to 100 mm Hg, were initially given 25 mg hydrochlorthiazide alone. After treatment for 3 months 10 mg pindolol was also given to 16 of them as the diastolic blood pressure had not been reduced to less than or equal to 90 mm Hg. After 3 months treatment on hydrochlorthiazide alone there was a significant increase in serum cholesterol, low density lipoprotein cholesterol and triglyceride concentrations, and a decrease in high density lipoprotein cholesterol concentration, and this pattern persisted after a further 3 months on the single drug regimen. In contrast, in those patients who received additional treatment with pindolol after the first 3 months, there was a significant decrease in the low density lipoprotein cholesterol and an increase in high density lipoprotein cholesterol during the following 3 months. Thus, the addition of pindolol to hydrochlorthiazide therapy appeared to reverse the negative effects on the lipid profile induced by the diuretic alone.