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.

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.

Predictivity of standardized and controlled permeation studies: Ex vivo - In vitro - In vivo correlation for sublingual absorption of propranolol.

In preclinical drug development, ex vivo and in vitro permeability studies are a decisive element for specifying subsequent development steps. In this context, reliability, physiological alignment and appropriate in vivo correlation are mandatory for predictivity regarding drug absorption. Especially in oromucosal drug delivery, these prerequisites are not adequately met, which hinders its progressive development and results in the continuous need for animal experiments. To address current limitations, an innovative, standardized, and controlled ex vivo permeation model was applied. It is based on Kerski diffusion cells embedded in automated sampling and coupled to mass spectrometric quantification under physiologically relevant conditions. This study aimed to evaluate the predictivity of the developed model using porcine mucosa (ex vivo) in relation to data of sublingual propranolol absorption (in vivo). In addition, the usefulness of biomimetic barriers (in vitro) as a replacement for porcine mucosa was investigated. Therefore, solubility and permeability studies considering microenvironmental conditions were conducted and achieved good predictivity (R2 = 0.997) for pH-dependent permeability. A multiple level C correlation (R2 ≥ 0.860) between obtained permeability and reported pharmacokinetic animal data (AUC, Cmax) was revealed. Furthermore, a point-to-point correlation was demonstrated for several sublingual formulations. The successful IVIVC confirms the standardized ex vivo model as a viable alternative to animal testing for estimating the in vivo absorption behavior of oromucosal pharmaceuticals.

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.

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.

A Review on Pharmacokinetic and Pharmacodynamic Drug Interactions of Adrenergic ß-blockers with Clinically Relevant Drugs-An Overview.

Adrenergic ß-blockers are used to treat many conditions, including hypertension, cardiac arrhythmias, heart failure, angina pectoris, migraine, and tremors. The majority of the ß-blockers including Propranolol, Metoprolol, Acebutolol, Alprenolol, Betaxolol, Carvedilol, Nebivolol and Oxprenolol are metabolised majorly by CYP2D6, and Bisoprolol is primarily metabolised by CYP3A4 enzymes. The drugs inhibiting or inducing them may alter the pharmacokinetics of those ß-blockers. The plasma concentrations of Propranolol might be elevated by the concomitant use of drugs, such as SSRIs (Fluoxetine, Paroxetine), SNRIs (Duloxetine) and Cimetidine, while the plasma concentrations of Metoprolol increased by the concurrent use of SSRIs (Fluoxetine, Paroxetine), Amiodarone, Celecoxib, Cimetidine, Terbinafine, and Diphenhydramine. ß-blockers can also interact pharmacodynamically with drugs, including fluoroquinolones, antidiabetic agents and NSAIDs. In addition, ß-blockers may interact with herbs, such as curcumin, Ginkgo biloba, Schisandra chinensis, green tea, guggul, hawthorn, St. John's wort and Yohimbine. This article focuses on clinically relevant drug interactions of ß-blockers with commonly prescribed medications. In addition to Pharmacokinetics and Pharmacodynamics of the drug interactions, recommendations for clinical practice are highlighted. The prescribers and the pharmacists are needed to be aware of the drugs interacting with ß-blockers to prevent possible adverse drug interactions.

Development and evaluation of a physiologically based pharmacokinetic model to predict carvedilol-paroxetine metabolic drug-drug interaction in healthy adults and its extrapolation to virtual chronic heart failure patients for dose optimization.

Purpose: The metabolic drug-drug interactions (mDDIs) are one of the most important challenges faced by the pharmaceutical industry during the drug development stage and are frequently associated with labeling restrictions and withdrawal of drugs. The capacity of physiologically based pharmacokinetic (PBPK) models to absorb and upgrade with the newly available information on drug and population-specific parameters, makes them a preferred choice over the conventional pharmacokinetic models for predicting mDDIs.Method: A PBPK model capable of predicting the stereo-selective disposition of carvedilol after administering paroxetine by incorporating mechanism (time) based inhibition of CYP2D6 and CYP3A4 was developed by using the population-based absorption, distribution, metabolism and elimination (ADME) simulator, Simcyp®.Results: The model predictions for both carvedilol enantiomers were in close agreement with the observed PK data, as the ratios for observed/predicted PK parameters were within the 2-fold error range. The developed PBPK model was successful in capturing an increase in exposures of R and S-carvedilol, due to the time-based inhibition of CYP2D6 enzyme caused by paroxetine.Conclusion: The developed model can be used for exploring complex clinical scenarios, where multiple drugs are given concurrently, particularly in diseased populations where no clinical trial data is available.

Development and Evaluation of a Physiologically Based Pharmacokinetic Drug-Disease Model of Propranolol for Suggesting Model Informed Dosing in Liver Cirrhosis Patients.

AIM: The study was aimed to understand the underlying causes for the differences in propranolol pharmacokinetics (PK) between healthy and cirrhosis populations by using a systematic whole-body physiologically based pharmacokinetic (PBPK) model-building approach for suggesting model informed propranolol dosing in liver cirrhosis patients with different stages of disease severity. METHODS: A whole-body PBPK model was developed by using population simulator PK-Sim® by using reported physicochemical and clinical data for propranolol in healthy and liver cirrhosis populations. The model evaluation was done by visual verification and comparison of PK parameters using their observed/predicted ratios (Robs/pred). RESULTS: The developed model has effectively described the disposition of propranolol after intravenous and oral application in healthy and liver cirrhosis populations. All the model predictions were comparable to the observed clinical data and the Robs/pred for all the PK parameters were within a 2-fold range. A significant increase in plasma concentration of propranolol and decrease in drug clearance was observed in progressive stages of liver cirrhosis. The developed model after evaluation with the reported clinical PK data was used for suggesting model informed propranolol dosing in different stages of liver cirrhosis based on systemic unbound drug concentration. CONCLUSION: The developed PBPK model has successfully described propranolol PK in healthy and cirrhosis populations after IV and oral administration. The evaluated PBPK propranolol-cirrhosis model can have many implications in predicting propranolol dosing in liver cirrhosis patients with different stages of disease severity.

Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice.

BACKGROUND: Due to blocking ß-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice. MATERIALS AND METHODS: As a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography-mass spectrometry. RESULTS: Sotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80-100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study. CONCLUSION: Sotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.

Urinary Excretion of Nadolol as a Possible In Vivo Probe for Drug Interactions Involving P-Glycoprotein.

Nadolol is a hydrophilic and nonselective ß-adrenoceptor blocker with a bioavailability of 30%, relatively longer half-life, negligible metabolism, and predominant renal excretion. Previous studies have reported that nadolol is a substrate of P-glycoprotein, and the coadministration with itraconazole, a typical P-glycoprotein inhibitor, results in elevated plasma concentrations and cumulative urinary excretion of nadolol. In this study, we assessed whether measurements of urinary-excreted nadolol can be an alternative method of plasma pharmacokinetics for P-glycoprotein-mediated drug interactions in humans. We reanalyzed the pooled data set of plasma concentration and urinary excretion of nadolol from our previous clinical studies in a total of 32 healthy Japanese adults. The area under the plasma concentration-time curve from 0 to infinity (AUC0-∞ ) of nadolol in individual subjects was significantly correlated with the maximum plasma concentration (r = 0.80, P < .01) and the cumulative amount excreted into urine (Ae ) at 4 (r = 0.51, P = .01), 8 (r = 0.63, P < .01), 24 (r = 0.75, P < .01), and 48 (r = 0.77, P < .01) hours. Significant correlations were also observed between the AUC and Ae during the same respective periods. In the drug interactions of nadolol with itraconazole, rifampicin, a well-known P-glycoprotein inducer, or grapefruit juice, there were significant correlations between the differences in AUC0-48 and those in Ae, 0-48 from the controls in individual subjects. These results suggest that the measurements of urinary excretion of nadolol can be employed as a sensitive and reliable alternative to plasma pharmacokinetics for the evaluation of P-glycoprotein-mediated drug interactions.

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.

Low-volume LC-MS/MS method for the pharmacokinetic investigation of carvedilol, enalapril and their metabolites in whole blood and plasma: Application to a paediatric clinical trial.

Evidence-based pharmacotherapy with carvedilol and enalapril in children suffering from heart failure is insufficient owing to limited pharmacokinetic data. Although a few data sets regarding enalapril, its metabolite enalaprilat and carvedilol in children have been published, pharmacokinetic data on carvedilol metabolites are missing. However, for both drug substances, their active metabolites contribute substantially to drug efficacy. As data can hardly be derived from adults owing to the unknown impacts of enzymatic maturation and ontogeny during childhood, customised assays are important to facilitate paediatric evidence-based pharmacotherapy. Considering ethical paediatric constraints, a low-volume liquid chromatography coupled to mass spectrometry (LC-MS/MS) assay was developed using whole blood or plasma for the quantification of enalapril, enalaprilat, carvedilol, O-desmethyl carvedilol, 4- and 5-hydroxyphenyl carvedilol as well as 3- and 8-hydroxy carvedilol. To facilitate broader applications in adults, the elderly and children, a wide calibration range-between 0.024/0.049 and 50.000 ng/ml-was achieved with good linearity (r ≥ 0.995 for all analytes). In compliance with international bioanalytical guidelines, accuracy, precision, sensitivity and internal standard normalised matrix effects were further successfully validated with the exception of those for 3-hydroxy carvedilol, which was therefore assessed semi-quantitatively. Distinct haematocrits did not impact matrix effects or recoveries when analysing whole blood. Blood-to-plasma ratios were determined for all analytes to form the basis for pharmacokinetic modelling. Finally, incurred sample reanalysis of paediatric samples confirmed the reproducibility of the developed low-volume LC-MS/MS method during study sample analysis. The assay facilitates the reliable generation of important data and contributes towards a safe drug therapy in children.

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.

Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults.

BACKGROUND: To study the pharmacokinetic and -dynamic behavior of landiolol in the presence of dobutamine in healthy subjects of European ancestry. METHODS: We conducted a single-center, prospective randomized study in 16 healthy subjects each receiving an infusion of dobutamine sufficient to increase heart rate by 30 bpm followed by a 60 min infusion of 10 µg/kg/min landiolol. RESULTS: Dobutamine-induced increases in heart rate were stable for at least 20 min before a 60 min landiolol- infusion was started. The dobutamine effects were rapidly antagonized by landiolol within 16 min. A further slight decrease in heart rate during 20-60 min of the landiolol infusion occurred as well. Upon termination of landiolol infusion, heart rate and blood pressure recovered rapidly in response to the persisting dobutamine infusion but did not return to the maximum values before landiolol infusion. The pharmacokinetic parameters of landiolol in presence of dobutamine showed a short half-life (3.5 min) and a low distribution volume (0.3 l/kg). No serious adverse events were observed. CONCLUSION: Landiolol can antagonize the dobutamine-induced increases in heart rate and blood pressure in a fast way. A rapid bradycardic effect until steady-state plasma levels is followed by a slow heart rate reduction. The latter can be attributed to an early desensitization to dobutamine. Consequently, after termination of landiolol, the heart rate did not achieve maximum pre-landiolol values. The pharmacokinetics of landiolol during dobutamine infusion are similar when compared to short- and long-term data in Caucasian subjects. Landiolol in the given dose can thus serve as an antagonist of dobutamine-induced cardiac effects. TRIAL REGISTRATION: Registration number 2010-023311-34 at the EU Clinical Trials Register, registration date 2010-12-21.

Application of Statistical Tooling Techniques for Designing of Carvedilol Nanolipid Transferosomes and its Dermatopharmacokinetic and Pharmacodynamic Studies.

BACKGROUND: The hypothesis is to augment the bioavailability and therapeutic potential of low bioavailable Carvedilol (25-35%) through Nanostructured Lipid Carrier (NLC) loaded Transdermal patch (Nanolipid Transferosomes). METHODS: Box-Behnken design was designed to formulate NLC through a hot homogenization technique. About 17 formulations (C1-C17) were formulated by varying the critical material attribute and critical process parameter. Optimization was done based on its critical quality attributes like particle size, zeta potential and entrapment efficiency. Selected NLC (C16) has been fabricated into a transdermal patch through solvent evaporation technique and estimated for thickness, weight variation, moisture content, folding endurance, drug content, in vitro drug release, ex vivo skin permeation studies 48 hrs, in vitro drug release kinetic studies and skin irritation studies. In vivo pharmacokinetics and pharmacodynamic study parameters were compared between carvedilol loaded NLC transdermal patch and a conventional formulation (Coreg CR). RESULTS: NLC (C16) was selected as the best formulation based on desirable, less particle size (201.1 ± 2.02 nm), more zeta potential (-37.2 ± 1.84mV) and maximum entrapment efficiency (87.54 ± 1.84%). Experimental investigations of in vivo dermatopharmacokinetic data shown statistically significant changes (p<0.05) in the parameter (increased AUC0-α, MRT with decreased Cmax, Tmax) when administered through the transdermal patch and on compared to the conventional dosage form. It was observed that there was a significant change with p<0.05 among the pharmacokinetic factors of conventional Carvedilol formulation, Carvedilol NLC and Carvedilol NLC loaded Transdermal patch with a maximum time of peak plasma concentration (Tmax) of 4 hrs, 8 hrs and 8 hrs; maximum peak plasma concentration (Cmax) of 0.258 µg/ml, 0.208 µg/ml and 0.108 µg/ml. Area Under Curve (AUC0-α) was established to be 125.127 µg/ml/h, 132.576 µg/ml.h and 841.032 µg/ml.h. Mean Residence Time (MRT0- α) of the drug was established to be 17 hrs, 19 hrs and 82 hrs, respectively. This data reveals the impact of NLC on the enhancement of bioavailability through a transdermal patch. In vivo pharmacodynamic studies confirm that NLC loaded transdermal patch (Nanolipid Transferosomes) shows a significant control in blood pressure for 48 hrs when compared to the conventional dosage form. CONCLUSION: This research data concludes that NLC loaded transdermal patch (Nanolipid Transferosomes) was a suitable candidate to enhance the bioavailability of low bioavailable drug-like Carvedilol. Lay Summary: It was inferred from the literature that NLC filled transdermal patches were a novel strategy to increase the solubility and permeability of Carvedilol, which has less bioavailability. It reveals that there was no reproducible preparation for the NLC. It also reveals that the option of formulation and process parameters for the formation of NLC is not clearly justified. On account of this, an uniquely validated and optimized formulation technique was developed for NLC with low soluble and poorly bioavailable carvedilol, tested in Albino wistar rats for enhancement of bioavailability, the same study has been performed and proved.

Evaluation of drug therapy problems, medication adherence and treatment satisfaction among heart failure patients on follow-up at a tertiary care hospital in Ethiopia.

BACKGROUND: Drug therapy problems (DTPs) are major concerns of healthcare and have been identified to contribute to negative clinical outcomes. The occurrence of DTPs in heart failure patients is associated with worsening of outcomes. The aim of this study was to assess DTPs, associated factors and patient satisfaction among ambulatory heart failure patients at Tikur Anbessa Specialized Hospital (TASH). METHODS: A hospital based prospective cross-sectional study was conducted on 423 heart failure patients on follow up at TASH. Data was collected through patient interview and chart review. Descriptive statistics, binary and multiple logistic regressions were used for analyses and P < 0.05 was used to declare association. RESULTS: Majority of the patients were in NYHA class III (55.6%) and 66% of them had preserved systolic function. DTPs were identified in 291(68.8%) patients, with an average number of 2.51±1.07.per patient. The most common DTPs were drug interaction (27.3%) followed by noncompliance (26.2%), and ineffective drug use (13.7%). ß blockers were the most frequent drug class involved in DTPs followed by angiotensin converting enzyme inhibitors. The global satisfaction was 78% and the overall mean score of treatment satisfaction was 60.5% (SD, 10.5). CONCLUSION: Prevalence of DTPs as well as non-adherence among heart failure patients on follow up is relatively high. Detection and prevention of DTPs along with identifying patients at risk can save lives, help to adopt efficient strategies to closely monitor patients at risk, enhance patient's quality of life and optimize healthcare costs.

Pharmacogenetic factors affecting ß-blocker metabolism and response.

INTRODUCTION: ß-blockers are among the most widely prescribed of all drugs, used for treatment of a large number of cardiovascular diseases. Herein we evaluate literature pertaining to pharmacogenetics of ß-blocker therapy, provide insight into the robustness of the genetic associations, and determine the appropriateness for translating these genetic associations into clinical practice. AREAS COVERED: A literature search was conducted using PubMed to collate evidence on associations between CYP2D6, ADRB1, ADRB2, and GRK5 genetic variation and drug-response outcomes in the presence of ß-blocker exposure. Pharmacokinetic, pharmacodynamic, and clinical outcomes studies were included if genotype data and ß-blocker exposure were documented. EXPERT OPINION: Substantial data suggest that specific ADRB1 and GRK5 genotypes are associated with improved ß-blocker efficacy and have potential for use to guide therapy decisions in the clinical setting. While the data do not justify ordering a CYP2D6 pharmacogenetic test, if CYP2D6 genotype is available in the electronic health record, there may be clinical utility for understanding dosing of ß-blockers.

Intermittent ß-adrenergic blockade downregulates the gene expression of ß-myosin heavy chain in the mouse heart.

Expression of the ß-myosin heavy chain (ß-MHC), a major component of the cardiac contractile apparatus, is tightly regulated as even modest increases can be detrimental to heart under stress. In healthy hearts, continuous inhibition of ß-adrenergic tone upregulates ß-MHC expression. However, it is unknown whether the duration of the ß-adrenergic inhibition and ß-MHC expression are related. Here, we evaluated the effects of intermittent ß-blockade on cardiac ß-MHC expression. To this end, the ß-blocker propranolol, at the dose of 15mg/kg, was administered once a day in mice for 14 days. This dosing schedule caused daily drug-free periods of at least 6 h as evidenced by propranolol plasma concentrations and cardiac ß-adrenergic responsiveness. Under these conditions, ß-MHC expression decreased by about 75% compared to controls. This effect was abolished in mice lacking ß1- but not ß2-adrenergic receptors (ß-AR) indicating that ß-MHC expression is regulated in a ß1-AR-dependent manner. In ß1-AR knockout mice, the baseline ß-MHC expression was fourfold higher than in wild-type mice. Also, we evaluated the impact of intermittent ß-blockade on ß-MHC expression in mice with systolic dysfunction, in which an increased ß-MHC expression occurs. At 3 weeks after myocardial infarction, mice showed systolic dysfunction and upregulation of ß-MHC expression. Intermittent ß-blockade decreased ß-MHC expression while attenuating cardiac dysfunction. In vitro studies showed that propranolol does not affect ß-MHC expression on its own but antagonizes catecholamine effects on ß-MHC expression. In conclusion, a direct relationship occurs between the duration of the ß-adrenergic inhibition and ß-MHC expression through the ß1-AR.

In-situ Intestinal Absorption and Pharmacokinetic Investigations of Carvedilol Loaded Supersaturated Self-emulsifying Drug System.

BACKGROUND: Carvedilol (CD), a non-selective beta-blocker, is indicated for the management of mild to moderate congestive heart failure. After oral administration, CD is rapidly absorbed with an absolute bioavailability of 18-25% because of low solubility and extensive first-pass metabolism. OBJECTIVE: The present investigation focused on enhanced oral delivery of CD using supersaturated self-emulsifying drug delivery (SEDDS) system. METHODS: Optimized SEDDS consisted of a blend of Oleic acid and Labrafil-M2125 as an oil-phase, Cremophor-RH40, polyethylene glycol-400 and HPMC-E5 as a surfactant, co-surfactant and supersaturation promoter respectively. Formulations were characterized for physical characteristics, invitro release in simulated and biorelevant dissolution media, intestinal permeability and bioavailability studies in Wistar rats. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis, scanning electron microscopy (SEM) studies were used to confirm the crystalline nature and shape of the optimized formulation. RESULTS: DSC and XRD, SEM studies showed that the drug was in amorphous form, and droplets were spherical in shape. Dissolution studies clearly showed distinct CD release in compendial and biorelevant dissolution media. The results from permeability and in-vivo studies depicted 2.2-folds and 3.2-folds increase in permeability and bioavailability, respectively from supersaturated SEDDS in comparison with control. CONCLUSION: The results conclusively confirmed that the SEDDS formulation could be considered as a new alternative delivery vehicle for the oral supply of CD. Lay Summary: Carvedilol (CD) is a non-selective antihypertensive drug with poor oral bioavailability. Previously, various lipid delivery systems were reported with enhanced oral delivery. We developed suprsaturable SEDDS formulation with immediate onset of action. SEDDS formulation was developed and optimized as per the established protocols. The optimized SEDDS formulation was stable over three months and converted to solid and supersaturated SEDDS. The results from permeability and in-vivo studies demonstrated an enhancement in permeability and bioavailability from supersaturated SEDDS in comparison with control. The results conclusively confirmed that the SEDDS formulation could be considered as a new alternative delivery vehicle for the oral administration of CD.