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)

The beta-adrenergic blocking agent, timolol, administered to resting rabbits as an i.v. bolus (0.125 mg/kg) sustained by a 2-hr infusion at 0.0625 mg/kg/hr, caused significant depression of plasma renin activity (PRA) to 49% of the control level. Significant correlations emerged between the fall in mean blood pressure and changes in both heart rate and PRA. Timolol also antagonized isoprenaline-induced renin release. In anaesthetized normal rats, timolol (0.2 mg/kg i.p.) suppressed mean plasma renin concentration (PRC) to 16% of the pre-treatment value. Furthermore, the mean PRC of normal rats, bled immediately after decapitation, to avoid stimulating renin secretion, was reduced by 55% one hr after i.p. injection of timolol. The potency of timolol in this respect was 8 times that of dl-propranolol. Thus, in rabbits and rats, timolol effectively depresses both basal and stimulated plasma renin levels.
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PMID:Suppression of renin release by timolol. 0 74

It has been found that D-timolol is equipotent or slightly less potent than L-timolol to lower the intraocular pressure (IOP) in normotensive rabbits, water loaded ocular hypertensive rabbits, alpha-chymotrypsin induced glaucoma rabbits, hypertonic saline infused IOP recovery model of rabbits, normotensive human volunteers, glaucoma patients and ocular hypertensive human individuals. Although L-timolol has been used widely for the treatment of glaucoma and ocular hypertension, it produces numerous side effects including cardiovascular disturbances, asthmatic attack, psychological depression, etc. Since D-timolol has much weaker affinity toward beta-adrenergic receptors, it was found to have 1/80-1/300 the beta-adrenergic blocking potency of L-timolol to block beta-adrenergic receptors in guinea pig tracheal preparations and 1/90 of L-timolol to block beta-adrenergic receptors in guinea pig atrial preparations. As a result, D-timolol showed no subjective nor objective side effects on pupil size, conjunctiva, cornea, blood pressure and pulse rate. Further, D-timolol was reported to increase retinal and choroid blood flow in rabbits without affecting overall ocular blood flow. On the contrary, L-timolol was found to significantly reduce the overall ocular blood flow and retinal and choroid blood flows in rabbits, although it might slightly increase the retinal blood flow in normotensive individuals. D-Timolol was well absorbed across the cornea as L-timolol and produced the duration of action as long as L-timolol. These results indicate that D-timolol could be a better agent than L-timolol for the treatment of glaucoma and ocular hypertension.
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PMID:Development of D-timolol for the treatment of glaucoma and ocular hypertension. 219 94

The effects of single oral doses of 10 mg felodipine and four beta-blockers (100 mg metoprolol, 5 mg pindolol, 80 mg propranolol, and 10 mg timolol) were evaluated alone and in combination in a 10-way crossover, double-blind, placebo-controlled trial in 10 healthy male volunteers randomized to the medication sequence according to a latin square design. Adverse effects were recorded from spontaneous complaints and investigator observations. Heart rate (HR), PR interval, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were measured supine, standing, and after treadmill exercise, before and 2 h after drug administration. The adverse effects experienced with felodipine were as expected for a vasodilator. Seven subjects mentioned complaints voluntarily on the combinations while three experienced side effects receiving felodipine or beta-blocker alone. Felodipine increased resting HR significantly. Timolol produced a greater depression of exercise heart rate than the other beta-blockers, indicating that the dose given was not equivalent to that of the other beta-blockers. Pindolol was ineffective in preventing the increase in supine HR produced by felodipine. Felodipine did not alter PR interval at any level of activity, but rate-corrected supine PR interval was prolonged slightly by felodipine. Metoprolol and timolol significantly prolonged standing PR interval. All beta-blockers prolonged exercise PR interval. Felodipine/beta-blocker combinations did not prolong PR interval more than beta-blockers alone. Prolonged PR interval was the result of reduced HR and direct inhibition of atrioventricular (AV) conduction. Only timolol and the timolol/felodipine combination lowered supine systolic blood pressure significantly. Timolol and all beta-blocker/felodipine combinations reduced exercise SBP significantly.
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PMID:Tolerance and cardiovascular effects of single dose felodipine/beta-blocker combinations in healthy subjects. 244 12

The effect of timolol on postganglionic cardiac sympathetic neural discharge, blood pressure, heart rate, and rhythm changes associated with acute coronary occlusion of the left anterior descending artery was examined and compared with the effects of the beta blockers practolol and metoprolol. Timolol (5 mg/kg, IV) was infused 15 minutes prior to coronary occlusion in cats anesthetized with alpha-chloralose. Control heart rate fell from 129 +/- 10 to 106 +/- 2 one minute prior to coronary occlusion and remained at 106 +/- 2 beats/minute in the minute prior to arrhythmia. Control blood pressure fell from 126 +/- 20 to 91 +/- 19 and stabilized at 99 +/- 19 mm Hg one minute prior to coronary occlusion. Mean time to arrhythmia and death was 4.7 +/- 2.3 and 68.0 +/- 51.0 minutes (P greater than .05 vs no drug), respectively. Three cats died and two were sacrificed six hours after coronary occlusion. Blood pressure fell to 86 +/- 20 mm Hg two minutes after coronary occlusion, rose to 95 +/- 23 mm Hg at ten minutes, and remained there for ten minutes. Timolol did not alter postganglionic cardiac sympathetic neural discharge prior to coronary occlusion. Two minutes after coronary occlusion, mean postganglionic cardiac sympathetic neural discharge was 128 +/- 27 and increased to 139 +/- 36 impulses/second (% control) 4 minutes after coronary occlusion. A similar trend was found for the data recorded in 15 nerves (eight cats) in which coronary occlusion was initiated without timolol. The data suggest that a difference exists among beta blockers because prior to coronary occlusion, the cardioselective drugs metoprolol (1, 5, and 10 mg/kg, IV) and practolol (8 mg/kg, IV) depressed postganglionic cardiac sympathetic neural discharge whereas noncardioselective timolol did not. Because all three beta blockers increased the times to arrhythmia and death (although the increase was significant only after metoprolol and practolol), the acute protective mechanism does not appear to be due primarily to a depression of spontaneous sympathetic neural discharge.
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PMID:The effect of beta blockers on cardiac neural discharge associated with coronary occlusion in the cat. 288 94

Antianginal efficacy and improved exercise performance with timolol, a new beta-adrenergic blocking agent, was assessed in 23 patients with chronic stable angina pectoris in an 11-week double-blind, placebo-controlled study. Twenty-two of the 23 subjects completed the open-label phase of this investigation (weeks 0 to 6) while receiving 10 to 30 mg of timolol twice daily to optimize exercise capacity. Weekly anginal episodes and nitroglycerin consumption declined from 8.9 +/- 9.1 episodes/week and 8.1 +/- 10.6 tablets/week, respectively, with placebo to 2.7 +/- 5.2 episodes/week and 2.6 +/- 6.0 tablets/week with optimal timolol dose (p less than 0.05). Resting heart rate (HR) and systolic blood pressure (SBP) also decreased from 75.2 +/- 14.0 beats/min and 139.1 +/- 15.7 mm Hg with placebo to 55.1 +/- 8.9 beats/min and 130.5 +/- 15.9 mm Hg with timolol (p less than 0.05). Peak exercise HR, peak exercise SBP, and peak exercise double product (HR X SBP) were significantly (p less than 0.05) reduced when evaluated 12 to 13 hours after administration of timolol compared with placebo (101.5 +/- 21.1 beats/min verus 193.3 +/- 96.2 beats/min, 161.5 +/- 26.7 mm Hg versus 175.6 + 20.8 mm Hg, and 16.6 +/- 5.1 X 10(-3) versus 21.7 +/- 5.4 X 10(-3), respectively). Exercise duration was prolonged from 263.3 +/- 90.2 seconds to 330.3 +/- 73.9 seconds (p less than 0.05), while time to onset of 1 mm S-T segment depression was delayed in 15 patients from 231.8 +/- 86.4 seconds to 298.7 +/- 68.4 seconds (p less than 0.05). During the double-blind phase (weeks 7 to 10), 8 subjects received timolol and 11 patients received placebo. Nitroglycerin consumption at weeks 8 and 10 and anginal frequency at week 8 were unchanged compared with initial placebo treatment. Resting HR, peak exercise HR, and peak exercise double product were significantly attenuated at weeks 8 and 10 in timolol patients compared with their initial placebo exposure. However, these variables were unchanged in placebo subjects compared with their initial placebo therapy. Exercise duration was again prolonged at week 8 in timolol subjects compared with initial placebo results (315.1 +/- 61.2 seconds versus 261.3 +/- 68.8 seconds, p less than 0.05), but not at week 10. Placebo patients demonstrated no difference at week 8 or 10 in exercise performance compared with initial placebo treatment. Timolol twice daily, therefore, is potentially useful in some patients with angina pectoris. Other patients may, however, require a shorter dose interval for optimal angina control and maximal improvement in exercise capacity.
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PMID:Antianginal efficacy and improved exercise performance with timolol. Twice-daily beta blockade in ischemic heart disease. 612 94

The nonspecific interaction of the beta-adrenergic blocking drugs, propranolol and timolol, with model and biological membranes has been investigated. Radioisotope measurements of the association of these drugs with dimyristoyl lecithin (DMPC) bilayers showed that both propranolol and timolol had a significantly greater molar association (mole of drug per mole of lipid) with DMPC above its phase transition temperature than below. Timolol had a much lower molar association with DMPC as compared with propranolol both above and below the phase transition temperature. For the DMPC model membrane system, the molar association of propranolol as measured by radioisotope and inferred from calorimetric studies was similar. Neutron diffraction utilizing propranolol deuterated in the naphthalene moiety showed that the naphthalene moiety of propranolol partitions into the hydrocarbon core of the DMPC lipid bilayer, and that the charged amine side chain is most likely positioned in the aqueous phospholipid head group region. For timolol, the association as measured by radioisotope methods was apparently greater than the partitioning inferred from calorimetric studies using freezing point depression analysis, suggesting a more complex interaction of timolol as compared with propranolol with the DMPC lipid bilayer. The association of propranolol and timolol with sarcoplasmic reticulum vesicles (SR) was similar to that with highly purified protein-depleted SR lipids, and DMPC above its phase transition. The association of propranolol with the SR membrane (mole of propranolol per mole of SR phospholipid) correlated with its ability to inhibit calcium uptake, whereas only a fraction of the total association of timolol with the SR membrane appeared to lead to inhibition of calcium uptake. These results suggest that the major nonspecific interactions of propranolol and timolol are with the SR membrane lipids, and that the magnitude of their interactions depends on both the lipid solubility of the drug and the physical state of the fatty acyl chains of the membrane. Both propranolol and timolol appear to perturb the functional properties of the calcium pump protein in the SR membrane (inhibition of ATP-induced calcium uptake) indirectly by partitioning into the bulk lipid matrix of the SR lipid bilayer, although other sites of interaction cannot be excluded.
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PMID:Comparisons of the interaction of propranolol and timolol with model and biological membrane systems. 688 69

Introduction of L-timolol maleate into the clinics for glaucoma treatment has been a great success as it produces relatively few side effects, such as miosis, ciliary spasm and headache, which are associated with the use of pilocarpine. Recent reports indicated, however, that L-timolol produces asthmatic attacks, cardiovascular suppression and central depression. D-Timolol was found to be as effective as L-timolol in lowering the intraocular pressure and aqueous humor production. However it was much less potent than L-timolol in inhibiting cardiac contractility and heart rate stimulated by isoproterenol and was less active in blocking beta-adrenergic receptors in tracheal muscle. It is suggested that the D-isomer of timolol could be used to treat glaucoma instead of L-isomer without producing untoward side effects in cardiovascular and bronchial tissues.
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PMID:Effects of D-timolol on intraocular pressure, heart rate, cardiac contractility, and tracheal muscle function. 718 3

The early cell kinetic response in the rat corneal and conjunctival epithelia was studied after a single topical application of dipivefrine, adrenaline and timolol with and without benzalkonium chloride. Benzalkonium chloride alone in different concentrations, 0.004%, 0.01%, 0.02% and 0.04%, respectively, was also evaluated. The stathmokinetic method and the tritiated thymidine technique were used to estimate the mitotic rate and the labelling index. Dipivefrine (Propine) gave a significant depression of the mitotic rate almost to the same extent as adrenaline in the corneal epithelium, whereas no changes were found in the limbal area and in the conjunctiva. Timolol (Oftan) with or without benzalkonium chloride, and benzalkonium chloride in different concentrations gave no obvious changes of the mitotic rate. No distinct drug effects on the labelling index were observed.
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PMID:Early cell kinetic effects of some drugs on the rat corneal and conjunctival epithelia. 901 71