-
Pharmaceutical Research Nov 2011To determine the influence of drug physicochemical properties on brain mitochondrial delivery of 20 drugs at physiological pH.
PURPOSE
To determine the influence of drug physicochemical properties on brain mitochondrial delivery of 20 drugs at physiological pH.
METHODS
The delivery of 8 cationic drugs (beta-blockers), 6 neutral drugs (corticosteroids), and 6 anionic drugs (non-steroidal anti-inflammatory drugs, NSAIDs) to isolated rat brain mitochondria was determined with and without membrane depolarization. Multiple linear regression was used to determine whether lipophilicity (Log D), charge, polarizability, polar surface area (PSA), and molecular weight influence mitochondrial delivery.
RESULTS
The Log D for beta-blockers, corticosteroids, and NSAIDs was in the range of -1.41 to 1.37, 0.72 to 2.97, and -0.98 to 2, respectively. The % mitochondrial uptake increased exponentially with an increase in Log D for each class of drugs, with the uptake at a given lipophilicity obeying the rank order cationic>anionic>neutral. Valinomycin reduced membrane potential and the delivery of positively charged propranolol and betaxolol. The best equation for the combined data set was Log % Uptake = 0.333 Log D + 0.157 Charge - 0.887 Log PSA + 2.032 (R(2) = 0.738).
CONCLUSIONS
Drug lipopohilicity, charge, and polar surface area and membrane potential influence mitochondrial drug delivery, with the uptake of positively charged, lipophilic molecules being the most efficient.
Topics: Adrenal Cortex Hormones; Adrenergic beta-Antagonists; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Chemical Phenomena; Computer Simulation; Drug Delivery Systems; Drug Evaluation, Preclinical; Male; Membrane Potential, Mitochondrial; Mitochondria; Molecular Targeted Therapy; Propranolol; Rats; Rats, Sprague-Dawley; Software
PubMed: 21796482
DOI: 10.1007/s11095-011-0532-4 -
British Journal of Pharmacology Feb 19931. The specificity of betaxolol, a beta-adrenoceptor antagonist, for beta 1- and beta 2-adrenoceptors was compared with that of other beta-antagonists, atenolol,... (Comparative Study)
Comparative Study
1. The specificity of betaxolol, a beta-adrenoceptor antagonist, for beta 1- and beta 2-adrenoceptors was compared with that of other beta-antagonists, atenolol, ICI-118551, butoxamine and (+/-)-propranolol, in the bovine trachea and heart by competitive interaction with [3H]-CGP12177 as a radioligand. 2. The radioligand Kd values were 0.75 +/- 0.12 and 1.60 +/- 0.11 nM in the trachea and heart, respectively, and the Bmax values were 34.00 +/- 4.41 and 21.54 +/- 2.94 fmol mg-1 protein, respectively. 3. Using ICI-118551, we determined the ratio of beta 1:beta 2-adrenoceptors in the trachea and heart to be approximately 29:71 and 56:44, respectively. 4. In the trachea, a beta 2-predominant tissue, betaxolol and atenolol were more selective for beta 1-adrenoceptor binding sites than beta 2-adrenoceptor binding sites, whereas ICI-118551 and butoxamine were more selective for beta 2-adrenoceptor binding sites. 5. The beta 1-selectivity of betaxolol was 2.2 and 2.7 fold higher than that of atenolol in the bovine trachea and heart. These findings suggest that betaxolol may be useful in the treatment of hypertension, cardiac arrhythmia and angina pectoris.
Topics: Animals; Betaxolol; Cattle; Heart; Organ Specificity; Radioligand Assay; Receptors, Adrenergic, beta; Trachea
PubMed: 8383566
DOI: 10.1111/j.1476-5381.1993.tb12829.x -
Yonsei Medical Journal Dec 2019Although the economic and mortality burden of atrial fibrillation (AF) is substantial, it remains unclear which treatment strategies for rate and rhythm control are most...
PURPOSE
Although the economic and mortality burden of atrial fibrillation (AF) is substantial, it remains unclear which treatment strategies for rate and rhythm control are most cost-effective. Consequently, economic factors can play an adjunctive role in guiding treatment selection.
MATERIALS AND METHODS
We built a Markov chain Monte Carlo model using the Korean Health Insurance Review & Assessment Service database. Drugs for rate control and rhythm control in AF were analyzed. Cost-effective therapies were selected using a cost-effectiveness ratio, calculated by net cost and quality-adjusted life years (QALY).
RESULTS
In the National Health Insurance Service data, 268149 patients with prevalent AF (age ≥18 years) were identified between January 1, 2013 and December 31, 2015. Among them, 212459 and 55690 patients were taking drugs for rate and rhythm control, respectively. Atenolol cost $714/QALY. Among the rate-control medications, the cost of propranolol was lowest at $487/QALY, while that of carvedilol was highest at $1363/QALY. Among the rhythm-control medications, the cost of pilsicainide was lowest at $638/QALY, while that of amiodarone was highest at $986/QALY. Flecainide and propafenone cost $834 and $830/QALY, respectively. The cost-effectiveness threshold of all drugs was lower than $30000/QALY. Compared with atenolol, the rate-control drugs propranolol, betaxolol, bevantolol, bisoprolol, diltiazem, and verapamil, as well as the rhythm-control drugs sotalol, pilsicainide, flecainide, propafenone, and dronedarone, showed better incremental cost-effectiveness ratios.
CONCLUSION
Propranolol and pilsicainide appear to be cost-effective in patients with AF in Korea assuming that drug usage or compliance is the same.
Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Cost-Benefit Analysis; Decision Trees; Drug Prescriptions; Heart Rate; Humans; Incidence; Male; Quality of Life; Republic of Korea
PubMed: 31769246
DOI: 10.3349/ymj.2019.60.12.1157 -
Cardiovascular Journal of Africa 2015Topical beta-blockers have a well-established role in the treatment of glaucoma. We aimed to investigate the outcome of patients who developed symptomatic...
BACKGROUND
Topical beta-blockers have a well-established role in the treatment of glaucoma. We aimed to investigate the outcome of patients who developed symptomatic atrioventricular (AV) block induced by topical beta-blockers.
METHODS
All patients admitted or discharged from our institution, the Siyami Ersek Training and Research Hospital, between January 2009 and January 2013 with a diagnosis of AV block were included in the study. Subjects using ophthalmic beta-blockers were recruited and followed for permanent pacemaker requirement during hospitalisation and for three months after discontinuation of the drug. A permanent pacemaker was implanted in patients in whom AV block persisted beyond 72 hours or recurred during the follow-up period.
RESULTS
A total of 1 122 patients were hospitalised with a diagnosis of AV block and a permanent pacemaker was implanted in 946 cases (84.3%) during the study period. Thirteen patients using ophthalmic beta-blockers for the treatment of glaucoma and no other rate-limiting drugs were included in the study. On electrocardiography, eight patients had complete AV block and five had high-degree AV block. The ophthalmic beta-blockers used were timolol in seven patients (55%), betaxolol in four (30%), and cartelol in two cases (15%). The mean duration of ophthalmic beta-blocker treatment was 30.1 ± 15.9 months. After drug discontinuation, in 10 patients the block persisted and a permanent pacemaker was implanted. During follow up, one more patient required pacemaker implantation. Therefore in total, pacemakers were implanted in 11 out of 13 patients (84.6%). The pacemaker implantation rate did not differ according to the type of topical beta-blocker used (p = 0.37). The presence of infra-nodal block on electrocardiography was associated with higher rates of pacemaker implantation.
CONCLUSION
Our results indicate that topical beta-blockers for the treatment of glaucoma may cause severe conduction abnormalities and when AV block occurs, pacemaker implantation is required in a high percentage of the patients.
Topics: Administration, Ophthalmic; Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Atrioventricular Block; Cardiac Pacing, Artificial; Electrocardiography; Female; Glaucoma; Heart Conduction System; Heart Rate; Hospitals, Teaching; Humans; Male; Middle Aged; Pacemaker, Artificial; Recurrence; Risk Factors; Time Factors; Treatment Outcome; Turkey
PubMed: 26659434
DOI: 10.5830/CVJA-2015-030 -
Clinical Ophthalmology (Auckland, N.Z.) 2012Oxidative stress induced retinal pigment epithelium (RPE) dysfunction is hypothesized to be fundamental in the pathogenesis of age-related macular degeneration (AMD)....
BACKGROUND
Oxidative stress induced retinal pigment epithelium (RPE) dysfunction is hypothesized to be fundamental in the pathogenesis of age-related macular degeneration (AMD). This study investigated whether vitamin C, vitamin C phosphate, vitamin E, propofol, betaxolol, and N-acetyl cysteine (NAC) protect human RPE cells from oxidative stress.
METHODS
ARPE-19 cells were pretreated with the compounds under investigation. The chemical oxidant tert-butyl hydroperoxide (t-BOOH) was used to induce oxidative stress. Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
RESULTS
Exposure to t-BOOH resulted in a dose- and time-dependent reduction in ARPE-19 cell viability. Compared with cells given t-BOOH alone, vitamin E and NAC pretreated cells had significantly improved viability, propofol and betaxolol pretreated cells had no significant difference in viability, and vitamin C and vitamin C phosphate pretreated cells had significantly reduced viability.
CONCLUSION
Of the compounds studied, only vitamin E and NAC significantly mitigated the effects of oxidative stress on RPE cells. Because of their potential therapeutic value for AMD patients, these and other RPE protective compounds continue to merit further investigation.
PubMed: 23055666
DOI: 10.2147/OPTH.S35139 -
Frontiers in Pharmacology 2021DEND syndrome is a rare channelopathy characterized by a combination of developmental delay, epilepsy and severe neonatal diabetes. Gain of function mutations in the...
DEND syndrome is a rare channelopathy characterized by a combination of developmental delay, epilepsy and severe neonatal diabetes. Gain of function mutations in the gene, encoding the K6.2 subunit of the I potassium channel, stand at the basis of most forms of DEND syndrome. In a previous search for existing drugs with the potential of targeting Cantú Syndrome, also resulting from increased I, we found a set of candidate drugs that may also possess the potential to target DEND syndrome. In the current work, we combined Molecular Modelling including Molecular Dynamics simulations, with single cell patch clamp electrophysiology, in order to test the effect of selected drug candidates on the K6.2 WT and DEND mutant channels. Molecular dynamics simulations were performed to investigate potential drug binding sites. To conduct studies, K6.2 Q52R and L164P mutants were constructed. Inside/out patch clamp electrophysiology on transiently transfected HEK293T cells was performed for establishing drug-channel inhibition relationships. Molecular Dynamics simulations provided insight in potential channel interaction and shed light on possible mechanisms of action of the tested drug candidates. Effective I inhibition was obtained with the pore-blocker betaxolol (IC values 27-37 μM). Levobetaxolol effectively inhibited WT and L164P (IC values 22 μM) and Q52R (IC 55 μM) channels. Of the SUR binding prostaglandin series, travoprost was found to be the best blocker of WT and L164P channels (IC 2-3 μM), while Q52R inhibition was 15-20% at 10 μM. Our combination of MD and inside-out electrophysiology provides the rationale for drug mediated I inhibition, and will be the basis for 1) screening of additional existing drugs for repurposing to address DEND syndrome, and 2) rationalized medicinal chemistry to improve I inhibitor efficacy and specificity.
PubMed: 35095528
DOI: 10.3389/fphar.2021.814066 -
Neuropsychopharmacology : Official... Jan 2017There is evidence for sex differences in cocaine addiction from both clinical and preclinical studies. In particular, preclinical studies indicate that females may be...
There is evidence for sex differences in cocaine addiction from both clinical and preclinical studies. In particular, preclinical studies indicate that females may be more sensitive than males to stress-induced drug seeking. The dorsal hippocampus (DH) is prominently involved in the stress response, as are the locus coeruleus norepinephrine (LC-NE) and dorsal raphe serotonin (DR 5-HT) systems. Moreover, DH receives strong inputs from LC-NE and DR 5-HT neurons. We hypothesized that the stress associated with non-reinforced drug seeking during early abstinence (on extinction day 1 (ED1)) may contribute to drug seeking via β-adrenergic and 5-HT neurotransmission in DH. We observed decreased drug-seeking behavior on ED1 following 10 mg/kg S-propranolol (β-adrenergic and 5-HT1A/1B receptor antagonist), R-propranolol (5-HT1A/1B receptor antagonist), or racemic propranolol in both male and female rats. ED1 increased Fos expression in DH, LC, and DR, and DH Fos was decreased by systemic S-propranolol. Based on these results, we investigated the effects of blocking 5-HT and β-adrenoceptor transmission in DH on drug seeking during ED1 by infusing a cocktail of WAY100635 plus GR127935 (5-HT1A/1B receptor antagonists), betaxolol plus ICI-118 551 (β1 and β2 antagonists), or S-propranolol alone. In males, WAY100635/GR127935 was most effective in reducing drug-seeking on ED1, whereas betaxolol/ICI-118 551 was ineffective. In contrast, S-propranolol was most effective in females in reducing drug seeking on ED1, and WAY100635/GR127935 and betaxolol/ICI-118 551 were each partially effective. Our results indicate that drug seeking during initial abstinence involves 5-HT and β-adrenergic signaling in female DH, but only 5-HT signaling in male DH.
Topics: Adrenergic beta-Antagonists; Animals; Cocaine; Dorsal Raphe Nucleus; Drug-Seeking Behavior; Female; Hippocampus; Locus Coeruleus; Male; Norepinephrine; Propranolol; Proto-Oncogene Proteins c-fos; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Receptors, Serotonin, 5-HT1; Self Administration; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Sex Characteristics; Stress, Psychological
PubMed: 27515792
DOI: 10.1038/npp.2016.150 -
Direct enantiomeric resolution of betaxolol with application to analysis of pharmaceutical products.Analytical Chemistry Insights Feb 2007A high-performance liquid chromatographic (HPLC) method has been developed for the separation and determination of S- and R-enantiomers of betaxolol in tablets and...
A high-performance liquid chromatographic (HPLC) method has been developed for the separation and determination of S- and R-enantiomers of betaxolol in tablets and ophthalmic preparations. Baseline resolution was achieved by using teicoplanin macrocyclic antibiotic chiral stationary phase (CSP) known as Chirobiotic T with fluorescence detection at excitation/emission wavelengths 275/305 nm. The polar ionic mobile phase (PIM) consists of methanol-glacial acetic acid-triethylamine, (100:0.020:0.025, v/v/v) has been used at a flow rate of 1.5 ml/min. All analytes with S-(-)-atenolol as internal standard were conducted at ambient temperature. The method is highly specific where another coformulated compounds did not interfere. The stability of betaxolol enantiomers under different degree of temperature also studied. The results showed that it is stable for at least 7 days at 70 degrees C. The method validated for its linearity, accuracy, precision and robustness. Experimental design was used during validation to evaluate method robustness. Using the chromatographic conditions described, S- and R-betaxolol were well resolved with mean retention times of 11.3 and 12.6 min, respectively. Linear response (r > 0.997) was observed over the range of 10-500 ng/ml of betaxolol enantiomers, with detection limit of 5 ng/ml. The recoveries of S- and R-betaxolol from tablets and ophthalmic preparation ranged from 97.4 to 101.4% and 98.0 to 102.0%, respectively. The mean relative standard deviation (R.S.D.%) for both enantiomers were 1.1-1.4% and 1.3-1.7% in tablets and ophthalmic solution, respectively.
PubMed: 19690633
DOI: No ID Found -
Ophthalmology Jun 2016To elucidate the temporal relationship between detection of glaucomatous optic disc progression, as assessed by fundus photography, and visual field progression. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To elucidate the temporal relationship between detection of glaucomatous optic disc progression, as assessed by fundus photography, and visual field progression.
DESIGN
Prospective, randomized, longitudinal trial.
PARTICIPANTS
Three hundred six study eyes with manifest glaucoma with field loss and 192 fellow eyes without any field defect at the start of the trial, from a total of 249 subjects included in the Early Manifest Glaucoma Trial (EMGT), were assessed.
METHODS
Evaluation of visual field progression and optic disc progression during an 8-year follow-up period. Three graders independently assessed optic disc progression in optic disc photographs. Visual field progression was assessed using glaucoma change probability maps and the EMGT progression criterion.
MAIN OUTCOME MEASURES
Time to detection of visual field progression and optic disc progression.
RESULTS
Among study eyes with manifest glaucoma, progression was detected in the visual field first in 163 eyes (52%) and in the optic disc first in 39 eyes (12%); in 1 eye (0%), it was found simultaneously with both methods. Among fellow eyes with normal fields, progression was detected in the visual field first in 28 eyes (15%) and in the optic disc first in 34 eyes (18%); in 1 eye (1%), it occurred simultaneously.
CONCLUSIONS
In eyes with manifest glaucoma, progression in the visual field was detected first more than 4 times as often as progression in the optic disc. Among fellow eyes without visual field loss at baseline, progression was detected first as frequently in the optic disc as in the visual field.
Topics: Adrenergic beta-1 Receptor Antagonists; Aged; Betaxolol; Combined Modality Therapy; Diagnostic Techniques, Ophthalmological; Disease Progression; Female; Follow-Up Studies; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Optic Disk; Optic Nerve Diseases; Photography; Prospective Studies; Time Factors; Trabeculectomy; Vision Disorders; Visual Field Tests; Visual Fields
PubMed: 26949119
DOI: 10.1016/j.ophtha.2016.01.039 -
Psychiatry Investigation May 2016The noradrenaline system is involved in the reward effects of various kinds of abused drugs. Betaxolol (BTX) is a highly selective β1-antagonist. In the present study,...
OBJECTIVE
The noradrenaline system is involved in the reward effects of various kinds of abused drugs. Betaxolol (BTX) is a highly selective β1-antagonist. In the present study, we evaluated the effect of BTX on methamphetamine (MAP)-induced conditioned place preference (CPP) and hyperactivity in mice.
METHODS
The mice (n=72) were treated with MAP or saline every other day for a total of 6 days (from day 3 to day 8; 3-times MAP and 3-times saline). Each mouse was given saline (1 mL/kg) or MAP (1 mg/kg, s.c.) or BTX (5 mg/kg, i.p.) or MAP with BTX (5 mg/kg, i.p.) 30 min prior to the administration of MAP (1 mg/kg, s.c.) every other day and paired with for 1 h (three-drug and three-saline sessions). We then compared the CPP score between the two groups. After the extinction of CPP, the mice were given BTX (5 mg/kg, i.p.) or saline (1 mL/kg) 24 h prior to a priming injection of MAP, and were then immediately tested to see whether the place preference was reinstated.
RESULTS
The repeated administration of BTX 30 min prior to the exposure to MAP significantly reduced the development of MAP-induced CPP. When BTX was administered 24 h prior to the CPP-testing session on day 9, it also significantly attenuated the CPP, but did not result in any change of locomotor activity. In the drug-priming reinstatement study, the extinguished CPP was reinstated by a MAP (0.125 mg/kg, s.c.) injection and this was significantly attenuated by BTX.
CONCLUSION
These findings suggest that BTX has a therapeutic and preventive effect on the development, expression, and drug-priming reinstatement of MAP-induced CPP.
PubMed: 27247598
DOI: 10.4306/pi.2016.13.3.316