Feasibility Study of Single-Photon Emission Computed Tomography with Iodine-123 Labeled Metaiodobenzylguanidine for Preclinical Evaluation of Labetalol as a ß-Adrenergic Receptor Blocker.

Among clinically used radiopharmaceuticals, iodine-123 labeled metaiodobenzylguanidine ([123I]mIBG) serves for diagnosing neuroendocrine tumors and obtaining images of myocardial sympathetic innervation. mIBG, a structural analogue of norepinephrine (NE), a neurotransmitter acting in peripheral and central nerves, follows a pathway similar to NE, transmitting signals through the NE transporter (NET) located at synaptic terminals. It moves through the body without decomposing, enabling noninvasive image evaluation. In this study, we aimed to quantify [123I]mIBG uptake in the adrenal glands using small animal single-photon emission computed tomography/computed tomography (SPECT/CT) images post [123I]mIBG administration. We investigated the possibility of assessing the effectiveness of ß-adrenergic receptor blockers by quantifying SPECT/CT images and biodistribution results to determine the degree of [123I]mIBG uptake in the adrenal glands treated with labetalol, a known ß-adrenergic receptor blocker. Upon intravenous administration of [123I]mIBG to mice, SPECT/CT images were acquired over time to confirm the in vivo distribution pattern, revealing a clear uptake in the adrenal glands. Labetalol inhibited the uptake of [123I]mIBG in cell lines expressing NET. A decrease in [123I]mIBG uptake in the adrenal glands was observed in the labetalol-treated group compared with the normal group through SPECT/CT imaging and biodistribution studies. These results demonstrate that SPECT/CT imaging with [123I]mIBG could be applicable for evaluating the preclinical efficacy of new antihypertensive drug candidates such as labetalol, a ß-adrenergic receptor blocker.

Rerouting cardiovascular management following gastric bypass surgery: Dose optimization of carvedilol using population-based analysis.

AIMS: A population-based pharmacokinetic (PK) modeling approach (PopPK) was used to investigate the impact of Roux-en-Y gastric bypass (RYGB) on the PK of (R)- and (S)-carvedilol. We aimed to optimize carvedilol dosing for these patients utilizing a pharmacokinetic/pharmacodynamic (PK/PD) link model. METHODS: PopPK models were developed utilizing data from 52 subjects, including nonobese, obese, and post- RYGB patients who received rac- carvedilol orally. Covariate analysis included anthropometric and laboratory data, history of RYGB surgery, CYP2D6 and CYP3A4 in vivo activity, and relative intestinal abundance of major drug- metabolizing enzymes and transporters. A direct effect inhibitory Emax pharmacodynamic model was linked to the PK model of (S)- carvedilol to simulate the changes in exercise- induced heart rate. RESULTS: A 2-compartmental model with linear elimination and parallel first-order absorptions best described (S)-carvedilol PK. RYGB led to a twofold reduction in relative oral bioavailability compared to nonoperated subjects, along with delayed absorption of both enantiomers. The intestinal ABCC2 mRNA expression increases the time to reach the maximum plasma concentration. The reduced exposure (AUC) of (S)-carvedilol post-RYGB corresponded to a 33% decrease in the predicted area under the effect curve (AUEC) for the 24-hour ß-blocker response. Simulation results suggested that a 50-mg daily dose in post-RYGB patients achieved comparable AUC and AUEC to 25-mg dose in nonoperated subjects. CONCLUSION: Integrated PK/PD modeling indicated that standard dosage regimens for nonoperated subjects do not provide equivalent ß-blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.

Beta-adrenergic glaucoma drugs reduce lymphatic clearance from the eye: A sequential photoacoustic imaging study.

Our study aims to determine whether the beta-adrenergic system is involved in the regulation of lymphatic drainage from the eye. For this purpose, we assessed the effect of 2 topical beta-adrenergic blockers, timolol and betaxolol, commonly used as glaucoma drugs, on lymphatic clearance of albumin from the aqueous humor to neck lymph nodes. Adult mice were treated with either topical timolol, a non-selective ß-blocker, 0.5% (n = 8), or topical betaxolol, a selective ß1-adrenergic blocker, 0.5% (n = 6) twice daily for 14 days and compared to respective control groups (n = 5 and n = 7). Changes in lymphatic clearance from the eye were assessed using a quantitative in vivo photoacoustic imaging approach. In all subjects, right eye and neck lymph nodes were longitudinally assessed by sequential photoacoustic imaging just prior to near-infrared dye injection into the anterior chamber of the eye, and 20 min, 2 and 4 h after injection. Repeat measurements of mean pixel intensities (MPIs) of right eyes and nodes were performed at all timepoints. The areas under the curves (AUC) were calculated and the AUC of the treated-group was compared to that of controls using the Mann-Whitney U test. The slopes of MPI of each region of interest over time were compared using the linear mixed model after adjusting for IOP decrease after treatment and other parameters such as sex and body weight. In the timolol-treated group, right neck nodes showed significant decrease in AUC signal intensity compared with controls (P = 0.003), and significant decrease in slope of MPI compared with controls (P = 0.0025). In the betaxolol-treated group, right neck nodes showed significant decrease in AUC signal intensity compared with controls (P = 0.02), and significant decrease in slope of MPI compared with controls (P = 0.0069). Topical treatment with timolol and betaxolol reduced lymphatic clearance of albumin from the aqueous humor to the neck lymph nodes. This finding may be relevant for the management of secondary glaucomas and inflammatory eye disease in which the clearance of accumulated proteins and antigen from the eye is important to disease recovery and sight protection. This study suggests that the beta-adrenergic system plays a role in the regulation of lymphatic clearance from the eye.

A narrative review of the importance of pharmacokinetics and drug-drug interactions of preventive therapies in migraine management.

OBJECTIVE: To review the pharmacokinetics of major classes of migraine preventives and the clinical implications of drug-drug interactions (DDIs) with the use of these therapies in migraine management. BACKGROUND: Preventive treatments for migraine are recommended for a large proportion of patients with frequent migraine attacks. These patients often exhibit a number of comorbidities, which may lead to the introduction of multiple concomitant therapies. Potential DDIs must be considered when using polytherapy to avoid increased risk of adverse events (AEs) or inadequate treatment of comorbid conditions. METHODS: A literature search was performed to identify pharmacokinetic properties and potential DDIs of beta-blockers, antiepileptic drugs, antidepressants, calcium channel blockers, gepants, and monoclonal antibody therapies targeting the calcitonin gene-related peptide pathway with medications that may be used for comorbid conditions. RESULTS: Most DDIs occur through alterations in cytochrome P450 isoenzyme activity and may be complicated by genetic polymorphism for metabolic enzymes. Additionally, drug metabolism may be altered by grapefruit juice ingestion and smoking. The use of migraine preventive therapies may exacerbate symptoms of comorbid conditions or increase the risk of AEs associated with comorbid conditions as a result of DDIs. CONCLUSIONS: DDIs are important to consider in patients with migraine who use multiple medications. The development of migraine-specific evidence-based preventive treatments allows for tailored clinical management that reduces the risk of DDIs and associated AEs in patients with comorbidities.

Extracorporeal treatment for poisoning to beta-adrenergic antagonists: systematic review and recommendations from the EXTRIP workgroup.

BACKGROUND: ß-adrenergic antagonists (BAAs) are used to treat cardiovascular disease such as ischemic heart disease, congestive heart failure, dysrhythmias, and hypertension. Poisoning from BAAs can lead to severe morbidity and mortality. We aimed to determine the utility of extracorporeal treatments (ECTRs) in BAAs poisoning. METHODS: We conducted systematic reviews of the literature, screened studies, extracted data, and summarized findings following published EXTRIP methods. RESULTS: A total of 76 studies (4 in vitro and 2 animal experiments, 1 pharmacokinetic simulation study, 37 pharmacokinetic studies on patients with end-stage kidney disease, and 32 case reports or case series) met inclusion criteria. Toxicokinetic or pharmacokinetic data were available on 334 patients (including 73 for atenolol, 54 for propranolol, and 17 for sotalol). For intermittent hemodialysis, atenolol, nadolol, practolol, and sotalol were assessed as dialyzable; acebutolol, bisoprolol, and metipranolol were assessed as moderately dialyzable; metoprolol and talinolol were considered slightly dialyzable; and betaxolol, carvedilol, labetalol, mepindolol, propranolol, and timolol were considered not dialyzable. Data were available for clinical analysis on 37 BAA poisoned patients (including 9 patients for atenolol, 9 for propranolol, and 9 for sotalol), and no reliable comparison between the ECTR cohort and historical controls treated with standard care alone could be performed. The EXTRIP workgroup recommends against using ECTR for patients severely poisoned with propranolol (strong recommendation, very low quality evidence). The workgroup offered no recommendation for ECTR in patients severely poisoned with atenolol or sotalol because of apparent balance of risks and benefits, except for impaired kidney function in which ECTR is suggested (weak recommendation, very low quality of evidence). Indications for ECTR in patients with impaired kidney function include refractory bradycardia and hypotension for atenolol or sotalol poisoning, and recurrent torsade de pointes for sotalol. Although other BAAs were considered dialyzable, clinical data were too limited to develop recommendations. CONCLUSIONS: BAAs have different properties affecting their removal by ECTR. The EXTRIP workgroup assessed propranolol as non-dialyzable. Atenolol and sotalol were assessed as dialyzable in patients with kidney impairment, and the workgroup suggests ECTR in patients severely poisoned with these drugs when aforementioned indications are present.

Practical instructions for using drugs in CT and MR cardiac imaging.

The progressive increase in numbers of noninvasive cardiac imaging examinations broadens the spectrum of knowledge radiologists are expected to acquire in the management of drugs during CT coronary angiography (CTCA) and cardiac MR (CMR) to improve image quality for optimal visualization and assessment of the coronary arteries and adequate MR functional analysis. Aim of this review is to provide an overview on different class of drugs (nitrate, beta-blockers, ivabradine, anxiolytic, adenosine, dobutamine, atropine, dipyridamole and regadenoson) that can be used in CTCA and CMR, illustrating their main indications, contraindications, efficacy, mechanism of action, metabolism, safety, side effects or complications, and providing advices in their use.

Development of carvedilol-loaded lipid nanoparticles with compatible lipids and enhanced skin permeation in different skin models.

The study aimed to develop lipid nanoparticles using excipients compatible with carvedilol (CARV) for enhanced transdermal drug delivery. Nanostructured lipid carriers (NLC) were successfully obtained and fully characterised. Franz diffusion cells were used for release and in vitro permeation studies in the porcine epidermis (EP) and full-thickness rat skin. NLC4 and NLC5 (0.5 mg/mL of CARV) presented small size (80.58 ± 1.70 and 116.80 ± 12.23 nm, respectively) and entrapment efficiency of 98.14 ± 0.79 and 98.27 ± 0.99%, respectively. CARV-loaded NLC4 and NLC5 controlled drug release. NLC4 allowed CAR permeation through porcine EP in greater amounts than NLC5, i.e. 11.83 ± 4.71 µg/cm2 compared to 3.06 ± 0.79 µg/cm2. NLC4 increased CARV permeation by 2.5-fold compared to the unloaded drug in rat skin studies (13.73 ± 4.12 versus 5.31 ± 1.56 µg/cm2). NLC4 seems to be a promising carrier for the transdermal delivery of CARV.

Formulation of carteolol chitosomes for ocular delivery: formulation optimization, ex-vivo permeation, and ocular toxicity examination.

Background:Conventional delivery systems like solution and suspension are commonly used for the treatment of ocular diseases but have low corneal residence time and hence the duration of effect is limited. These drawbacks of conventional systems can be reduced by preparing bioadhesive chitosan (CH) coated noisome.Methods: Niosomes (NIM) of carteolol (CT) were developed by the thin-film hydration method and optimised by the Box-Behnken statistical design. Further, the optimised CT-NIM was coated with CH to enhance the ocular residence time . The optimised formulation was evaluated for vesicle size, entrapment efficiency, and in-vitro drug release and transcorneal permeation, histopathology, etc.Results: CT-NIM-opt showed the vesicle size and entrapment efficiency of 235 ± 3.54 nm, and 70.45 ± 0.87%, respectively. DSC spectra exhibited that CT was completely encapsulated into the CH-CT-NIM matrix. Drug release from CH-CT-NIM-opt was more sustained (68.28 ± 4.2%) than CT-NIM (75.69 ± 4.5% in 12 h) and CT solution (99.89 ± 2.8% in 4 h). The CH-CT-NIM-opt represented a strong bio-adhesion (89.76 ± 3.6%) than CT-NIM-opt (15.65 ± 3.4%). The permeation flux exhibited 1.13-fold higher permeation than CT-NIM and 3.23 fold than CT solution. The corneal hydration was found to be within the limit value. The histopathology study exhibited no structural damage to the cornea . HET-CAM results showed zero scores indicating no bleeding or haemorrhage. CH-CT-NIM-opt was found to be isotonic and exhibited good stability when stored at 4 °C for the stated duration of time.Conclusion: The above findings suggested that NIM can be a potential carrier for the delivery of CT with better ocular residence time.

ß-blockers: Their new life from hypertension to cancer and migraine.

The pharmacological class of ß-blockers includes a plea of molecules with largely different pharmacokinetic and pharmacodynamic characteristics with a protective effect that may span far beyond the cardiovascular system. Although all these compounds share the pharmacological blockade of the adrenergic receptors, each of them is characterized by specific pharmacological properties, including selectivity of action depending on the adrenergic receptors subtypes, intrinsic sympathomimetic activity (ISA), lipid solubility, pharmacokinetic profile, and also other ancillary properties that impact their clinical effect. Their use in the treatment of hypertension has been extensively debated and at the moment a class indication is not present. However, in specific niche of patients, such as in those young individuals in which hypertension is mainly driven by a sympathetic hyperactivation, strong evidence pose ß-Blockers as a highly reasonable first-line treatment. Lipophilic ß-blockers, specifically propranolol and metoprolol, can cross the Blood Brain Barrier and have a Class A indication for the prophylactic treatment of migraine attacks. Moreover, since ß-adrenergic receptors affect the proliferative process of both cancer and immune cells, their blockade has been associated with metastasis reduction in several epithelial and solid organ tumors posing ß-Blockers as a new attractive, inexpensive and relatively safe therapeutic strategy in patients with several types of cancer. However, further dedicated prospective, randomized, placebo-controlled studies are needed to determine the real efficacy of these compounds.

New technique to reduce systemic side effects of timolol eye drops: The tissue press method-Cross-over clinical trial.

IMPORTANCE: Nasolacrimal occlusion (NLO) is effective in reducing systemic absorption of eye drop medication but it is difficult and often performed poorly. We propose an alternative easier and equally effective technique. BACKGROUND: To test the effectiveness of systemic absorption, we evaluated plasma concentration and ocular effects after topically administered timolol and compared to NLO. DESIGN: Cross-over trial carried out in Capital Eye Specialist, Wellington. PARTICIPANTS: A total of 21 subjects over 18 years without contraindications for topical beta-blocker medication and not using systemic beta-blockers. METHODS: During three clinic visits separated by at least one week, alternative approaches to reduce systemic eye drop absorption were tested. These were: (a) nasolacrimal (punctal) occlusion for 5 min, (b) tissue press method or (c) no intervention. Timolol plasma levels were measured 1 h after drop application. At each visit, baseline measurement of blood pressure, heart rate and intraocular pressure (IOP) were performed, and repeated 1 h after timolol 0.5% eye drop application. MAIN OUTCOME MEASURES: Comparison of timolol plasma concentration after each intervention. Secondary outcome measurements included effects on blood pressure, heart rate and IOP. RESULTS: Plasma timolol concentrations after tissue press method and NLO were significantly lower than those without intervention. Comparing tissue press method to NLO, there were no significant differences in plasma levels of timolol, blood pressure, heart rate or IOP. CONCLUSION AND RELEVANCE: The tissue press method is equally effective as NLO in reducing systemic absorption of timolol. It is also easier and faster to administer.

Effects of atorvastatin on talinolol absorption: A potential drug-drug interaction.

In this study, we aimed to determine the drug-drug interaction potential between atorvastatin (ATOR), and talinolol (TAL). Concentration-dependent effects of ATOR on the intestinal permeability of TAL were investigated by an in situ intestinal perfusion method. Dose-dependent effects of ATOR on TAL exposure were evaluated by measuring plasma concentrations after oral administration in rats. ATOR slightly changed the intestinal secretion of TAL in jejunum but not in colon. Plasma AUC levels of TAL were elevated by co-administration of ATOR at low and high doses whereas medium doses of ATOR resulted in a decrease in TAL bioavailability. However, these changes were not statistically significant. In our study, the pharmacokinetics of TAL were not affected by the concurrent use of ATOR in rats. In conclusion, it should be considered that complex interplay between the efflux and uptake transporters in the tissues and inhibition of these transporters by modulating agents may overshadow individual effects of each other.

Between an ugly truth and a perfect lie: Wiping off fearful memories using beta-adrenergic receptors antagonists.

Psychiatric disorders such as anxiety, phobias, and post-traumatic stress disorder are considered of high global prevalence. Currently, a therapeutic approach to treat these disorders using beta-blockers, which antagonize the beta-adrenergic receptors (B1, B2, and B3) is being studied. This approach claims that beta-blockers, such as propranolol, inhibit fear memory reconsolidation. However, there are several studies refuting such claims by discrediting their experimental design and pointing out both the drugs pharmacokinetic properties and confounding factors. In this review, we explore the different effects of central beta-adrenergic agonists and antagonists on the fear memory consolidation providing mixed-evidence, limitations, and future directions.

Antihypertensive Agents in the Dialysis Patient.

PURPOSE OF REVIEW: Hypertension and antihypertensive drug utilization are remarkably prevalent in ESRD patients. Management of blood pressure elevation in this population is complicated by many factors, including a multidimensional etiology, challenges in obtaining accurate and appropriately timed blood pressure measurements, highly specific drug dosing requirements, and a paucity of outcomes-based evidence to guide management decisions. The purpose of this review is to summarize and apply knowledge from existing clinical trials to enhance safe and effective use of antihypertensive agents in dialysis patients. RECENT FINDINGS: Two meta-analyses have established the benefit of antihypertensive therapy in ESRD. Data supporting the use of one antihypertensive class over another is less robust; however, beta-blockers have more clearly demonstrated improved cardiovascular outcomes in prospective randomized trials. Interdialytic home blood pressure monitoring has been demonstrated to be better associated with cardiovascular outcomes than clinic pre- or post-dialysis readings and should ideally be considered as a routine part of blood pressure management in this population. As data from small trials provides limited guidance for the management of hypertension in ESRD, more research is needed to guide medication selection and utilization. Specifically, large prospective randomized trails comparing cardiovascular outcomes of various medication classes and differing blood pressure targets are needed.

Prediction of Hepatic Clearance of Stereoselective Metabolism of Carvedilol in Liver Microsomes and Hepatocytes of Sprague-Dawley and Cytochrome P450 2D-Deficient Dark Agouti Rats.

Hepatic clearance (CLh) of carvedilol (CAR), which is eliminated via stereoselective metabolism by the CYP2D subfamily of cytochromes P450 (CYPs), was predicted using liver microsomes and hepatocytes from Sprague-Dawley (SD) rats and CYP2D-deficient Dark Agouti (DA) rats to determine the usefulness of prediction method. Plasma concentrations of CAR following intravenous injection to DA rats were higher than those in SD rats. The volume of distribution at steady state and total clearance (CLtot) of S-CAR were approximately two times greater than those of R-CAR in both strains. CLh predicted from in vitro studies using DA rat liver microsomes was different from that obtained from in vivo studies. In contrast, in vitro CLh prediction using DA rat hepatocytes was nearly identical to the CLh observed in DA rats in vivo, and was lower than that in SD rats. The predicted CLh in vitro using hepatocytes correlated well with the observed CLtot in vivo, which is expected to be nearly the same as CLh. These results suggest that in vitro metabolic studies using hepatocytes are more relevant with regard to stereoselectively predicting CLh of CAR than those using liver microsomes.

In Vitro Skin Retention and Drug Permeation through Intact and Microneedle Pretreated Skin after Application of Propranolol Loaded Microemulsions.

PURPOSE: Topical beta-blockers are efficacious for treating infantile hemangiomas, but no formulations have been specifically optimized for skin delivery. Our objective was to quantify skin concentrations and drug permeation of propranolol (a nonselective beta-blocker) after application of microemulsions to intact and microneedle pretreated skin. METHODS: Four propranolol-loaded microemulsions were characterized for droplet size, surface charge, conductivity, pH, drug solubility, and drug release. Skin concentrations and drug permeation through skin were quantified using LC-MS. Skin-to-receiver ratios were used to compare the microemulsion formulations to a drug-in-PBS solution. RESULTS: Propranolol solubility was significantly greater in microemulsions vs PBS. Cumulative drug release from the microemulsions over 24 h ranged from 13 to 26%. Skin concentrations and drug permeation through intact skin was significantly higher from PBS; however, the skin-to-receiver ratios were significantly higher for water-rich microemulsions compared to PBS or surfactant-rich microemulsions. Microneedle pretreatment significantly increased skin concentrations for all formulations. Skin-to-receiver ratios significantly increased after microneedle pretreatment for surfactant-rich microemulsions. CONCLUSIONS: Microemulsion formulation can be altered to elicit different drug delivery profiles through MN-treated skin. This could be advantageous for maximizing local skin drug concentrations and improving dosing schedules for infantile hemangioma treatment.

Pharmacokinetics and Pharmacodynamics of Low-, Intermediate-, and High-Dose Landiolol and Esmolol During Long-Term Infusion in Healthy Whites.

The pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of esmolol and landiolol, a new fast-acting cardioselective ß-blocker, were compared for the first time in Caucasian subjects in a prospective clinical trial. Twelve healthy volunteers received landiolol and esmolol by continuous infusion for 24 hours in a randomized crossover study using a dose-escalation regimen. Blood concentrations of drugs and metabolites, heart rate, blood pressure, ECG parameters, and tolerability were observed for 30 hours and compared. Drug blood concentrations and areas under the curve were dose-proportional. The half life of landiolol (4.5 minutes) was significantly shorter than that of esmolol (6.9 minutes). Volume of distribution and total clearance were lower for landiolol. Heart rate reduction was faster and more pronounced with landiolol and retained throughout the administration period; effects on blood pressure were not different. Landiolol turned out to be superior to esmolol with respect to pharmacokinetic and pharmacodynamic profile and local tolerability.

Role of (-)-epigallocatechin gallate in the pharmacokinetic interaction between nadolol and green tea in healthy volunteers.

PURPOSE: The aim of the present study is to investigate a possible role of a single dose of (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, for the pharmacokinetic interaction between green tea and nadolol in humans. METHODS: In a randomized three-phase crossover study, 13 healthy volunteers received single doses of 30 mg nadolol orally with water (control), or an aqueous solution of EGCG-concentrated green tea extract (GTE) at low or high dose. Plasma concentrations and urinary excretion of nadolol were determined up to 48 h. In addition, blood pressure and pulse rate were monitored. In vitro transport kinetic experiments were performed using human embryonic kidney 293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated substrate transport. RESULTS: Single coadministration of low and high dose GTE significantly reduced the plasma concentrations of nadolol. The geometric mean ratios with 90% CI for area under the plasma concentration-time curves from 0 to infinity of nadolol were 0.72 (0.56-0.87) for the low and 0.60 (0.51-0.69) for the high dose. There were no significant differences in Tmax, elimination half-life, and renal clearance between GTE and water phases. No significant changes were observed for blood pressure and pulse rate between phases. EGCG competitively inhibited OATP1A2-mediated uptake of sulphobromophthalein and nadolol with Ki values of 21.6 and 19.4 µM, respectively. CONCLUSIONS: EGCG is suggested to be a key contributor to the interaction of green tea with nadolol. Moreover, even a single coadministration of green tea may significantly affect nadolol pharmacokinetics.

Enhancement in Corneal Permeability of Dissolved Carteolol by Its Combination with Magnesium Hydroxide Nanoparticles.

We prepared magnesium hydroxide (MH) nanoparticles, and investigated their effect when combined with dissolved carteolol on the bioavailability and intraocular pressure (IOP)-reducing effect of carteolol. The carteolol was solved in saline containing additives (0.5% methylcellulose, 0.001% benzalkonium chloride, 0.5% mannitol; CRT-solution). MH nanoparticles were prepared by a bead mill method with additives. Then carteolol/MH microparticle and carteolol/MH nanoparticle fixed combinations (mCMFC and nCMFC) were prepared by mixing the CRT-solution and MH particles. The transcorneal penetration and IOP-reducing effect of carteolol was evaluated in rabbits. The mean particle size of mCMFC was 7.2 µm, and the particle size was reduced to 73.5-113.5 nm by the bead mill treatment. The MH particles in nCMFC remained in the nano size range for 8 days after preparation, and the amounts of lacrimal fluid and corneal damage were unchanged by repetitive instillation of nCMFC (twice a day for 4 weeks). The transcorneal penetration of carteolol was enhanced by the combination with MH nanoparticles, and the IOP-reducing effect of nCMFC was significantly higher than that of CRT-solution or mCMFC. In conclusion, we designed nCMFC, and showed that the high levels of dissolved carteolol can be delivered into the aqueous humor by the instillation of nCMFC. Combination with MH nanoparticles may achieve an enhancement of corneal penetration for water-soluble drugs. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma eye drugs.

Pharmacodynamic and -kinetic Behavior of Low-, Intermediate-, and High-Dose Landiolol During Long-Term Infusion in Whites.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of landiolol, a fast-acting cardioselective ß-blocker, were investigated for the first time in white subjects in a prospective clinical trial. Blood concentrations of landiolol and its metabolites, heart rate (HR), blood pressure (BP), and electrocardiogram parameters were studied in 12 healthy volunteers receiving continuous infusions of a new 12-mg/mL formulation of landiolol using a dose-escalation regimen (10 µg/kg BW/min for 2 hours, 20 µg/kg BW/min for 2 hours, 40 µg/kg BW/min for 20 hours, 6 hours follow-up). Landiolol blood concentrations were dose proportional. Time until steady state decreased with increasing doses. Pharmacokinetic parameters were t1/2 = 4.5 minutes, VD = 366 mL/kg, and total body clearance = 53 mL·kg·min. Maximal blood concentrations of the inactive main metabolite M1 were 10-fold higher than those of landiolol, with t1/2 = 126 minutes, VD = 811 mL/kg, and total body clearance = 4.5 mL·kg·min. HR reduction from baseline was fast (significant after 16 minutes) and sustained throughout the administration period. Systolic and diastolic BP reductions and electrocardiogram parameter changes were less pronounced and became significant only occasionally. Recovery after discontinuation of infusion was fast with little (HR) or no (BP) rebound. The new formulation showed excellent local and general tolerability.

Bolus application of landiolol and esmolol: comparison of the pharmacokinetic and pharmacodynamic profiles in a healthy Caucasian group.

PURPOSE: The aim of this prospective study was to compare in non-Asian subjects the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of two short-acting cardioselective ß1-adrenergic antagonists, landiolol and esmolol, after administration of three different bolus dosages. MATERIALS AND METHODS: We conducted a single-center, prospective, double-blinded, randomized study in three cross-over periods with 12 healthy subjects (7 women and 5 men, mean age of 24.5 ± 6.9 years) each receiving three doses of landiolol (0.1, 0.2, and 0.3 mg/kg BW) either in a newly developed concentrate i.v. formulation (Rapibloc® 20 mg/2 mL concentrate) or a lyophilized formulation, or three doses of esmolol (0.5, 1, and 1.5 mg/kg BW) in an i.v. formulation (Brevibloc® 100 mg/10 mL). PK and PD parameters, safety, and tolerability were assessed. FINDINGS: Results of the two landiolol formulations were reported previously and were similar. For the landiolol concentrate formulation and esmolol, maximum blood concentrations were rapidly reached (mean t max ranged between 1.8 and 3.0 min for landiolol and 1.8 to 2.4 min for esmolol). The parent drugs disappeared very fast from the blood stream, with a t 1/2 of 3.2 ± 1.2 (SD) minutes and 3.7 ± 2.1 (SD) minutes for the low doses of landiolol and esmolol, respectively. Despite comparable injection rates (0.1 or 0.5 mg/kg/15 s for landiolol and esmolol, respectively), the onset of significant heart rate reduction occurred earlier in response to landiolol (1 min) than in response to esmolol (2 min). In addition, significantly lower heart rate values were obtained at every dose level of landiolol, in comparison to esmolol (p < 0.05). Both compounds reduced the systolic blood pressure to a comparable degree. Especially at the highest dose, the duration of blood pressure reduction was longer under esmolol compared to landiolol. Seven mild to moderate adverse events occurred after administration of landiolol, and five occurred after administration of esmolol. No serious adverse events were reported in this study. IMPLICATIONS: Heart rate reduction induced by a new liquid formulation of landiolol occurred faster, was more pronounced, and lasted longer than the effects of corresponding standard esmolol doses. Both agents reduced systolic blood pressure to a comparable degree, but the blood pressure decrease lasted longer after esmolol infusion. The local tolerance and safety profiles of the two formulations were similar. In summary, compared to esmolol, landiolol shows a more prominent and pronounced bradycardic effect in relation to its blood pressure-lowering effect, an action profile that might be of specific advantage in the perioperative setting. TRIAL REGISTRATION: NCT01652898 and 2012-002127-14. https://clinicaltrials.gov/ct2/show/NCT01652898?term=landiolol&rank=7.