Phenibut: Review and Pharmacologic Approaches to Treating Withdrawal.

ß-Phenyl-γ-aminobutyric acid (phenibut) is an analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) that was first synthesized in Russia in the early 1960s. It is marketed as a nootropic (smart drug) to improve cognitive performance, and to treat generalized and social anxiety, insomnia, and alcohol withdrawal. The use of phenibut is legal in the USA and it is widely available online without a prescription. Increased public awareness of phenibut has led to a growing number of reports of acute intoxication and withdrawal. In this review, we describe the pharmacology of phenibut, the presentation and management of acute intoxication, and regulatory issues, placing particular emphasis on the treatment of acute withdrawal, for which there are no comparative studies. Among 29 cases of phenibut withdrawal, patients were successfully treated with baclofen, benzodiazepines, and phenobarbital, as individual agents or in various combinations. Ancillary medications included antipsychotics, dexmedetomidine, gabapentin, and pregabalin. After stabilization, a number of patients did well on baclofen tapers, whereas others were weaned off benzodiazepines or phenobarbital. Phenobarbital may be preferred over baclofen, or used as an added agent, in patients at risk for seizures. As long as phenibut remains legal, cases of phenibut intoxication and withdrawal are likely to increase. As urine or plasma drug screening for phenibut is not widely available, it is vital that clinicians obtain a detailed medication history in patients presenting to the emergency department with nonspecific symptoms that may represent phenibut intoxication or withdrawal. Further, clinicians may wish to consult an addiction specialist or toxicologist in these situations.

Limitations of fexofenadine limited sampling strategy using plasma concentrations and partial area under the concentration-time curve to estimate transporter activity in healthy adults.

OBJECTIVE: Fexofenadine is a probe drug used to phenotype P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3 activities. This study evaluated a limited sampling strategy using plasma concentrations and/or partial area under the concentration versus time curves (AUCs) to estimate systemic exposure and, potentially, P-gp and OATP1B1/3 activities. MATERIALS AND METHODS: Plasma concentration versus time data were obtained from 53 healthy adult participants (22 females) from four published studies. Participants were administered a single oral dose (120 mg) of fexofenadine during constitutive P-gp and OATP1B1/3 conditions. Concentration-time data were divided into a training (n = 18) and validation (n = 35) set. Backwards stepwise linear regression generated single-, 2-timepoint, and partial AUC limited sampling models (LSMs). Noncompartmental analysis methods were used to determine total AUC (AUC0-lNF) from intensive sampling. Coefficient of determination (r2) and bias and precision were assessed via relative percent mean prediction error (%MPE), relative percent mean absolute error (%MAE), and relative percent root mean square error (%RMSE). RESULTS: The geometric mean observed AUC0-INF was 1,680 ng×h/mL. The 2-, 5-, and 2- plus 5-hour LSMs met backwards stepwise linear regression significance (p < 0.15) to remain in the model but had unacceptable %RMSE (17 - 29%). The majority of partial AUC LSMs had unacceptable r2 (0.21 - 0.83), with all models having unacceptable %MAE (12 - 35%). CONCLUSION: Fexofenadine limited sampling strategy using single-timepoint, 2-timepoint, and partial AUCs were unable to accurately estimate AUC0-lNF and thus constitutive P-gp and OATB1B1/3 activities in healthy adults. Timepoints that were not measured or selected may have improved LSM performance.

Fexofenadine Plasma Concentrations to Estimate Systemic Exposure in Healthy Adults Using a Limited Sampling Strategy with a Population Pharmacokinetic Approach.

BACKGROUND: Fexofenadine is a recommended in vivo probe drug for phenotyping P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3 transporter activities. This study evaluated a limited sampling strategy using a population pharmacokinetic approach to estimate plasma fexofenadine exposure as an index of P-gp and OATP activities. METHODS: In a previous study, a single oral dose of fexofenadine (120 mg) was administered alone or in combination with grapefruit juice, Panax ginseng , or Echinacea purpurea to healthy adult participants. Serial plasma samples were collected up to 72 hours after administration and fexofenadine concentrations were measured. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Limited sampling models (LSMs) using single and 2-timepoint fexofenadine concentrations were compared with full profiles from intense sampling using empirical Bayesian post hoc estimations of systemic exposure derived from the population pharmacokinetic model. Predefined criteria for LSM selection and validation included a coefficient of determination (R 2 ) ≥ 0.90, relative percent mean prediction error ≥ -5 to ≤5%, relative percent mean absolute error ≤ 10%, and relative percent root mean square error ≤ 15%. RESULTS: Fexofenadine concentrations (n = 1520) were well described using a 2-compartment model. Grapefruit juice decreased the relative oral bioavailability of fexofenadine by 25%, whereas P. ginseng and E. purpurea had no effect. All the evaluated single timepoint fexofenadine LSMs showed unacceptable percent mean prediction error, percent mean absolute error, and/or percent root mean square error. Although adding a second time point improved precision, the predefined criteria were not met. CONCLUSIONS: Identifying novel fexofenadine LSMs to estimate P-gp and OATP1B1/3 activities in healthy adults for future transporter-mediated drug-drug interaction studies remains elusive.

Knowledge of Kratom among Alabama Pharmacists.

Kratom (Mitragyna speciosa) is a botanical substance whose leaves produce stimulant- and opioid-like effects. Kratom use has increased precipitously in the United States (U.S.) over the last decade, yet, in our experience, many pharmacists are unfamiliar with this herb. The purpose of this study was to assess pharmacists' awareness and knowledge of kratom. This cross-sectional study used an online questionnaire to preferentially solicit community pharmacists' knowledge of kratom and collect demographic information. The survey was sent via email to approximately 10,000 pharmacists, targeting those in the state of Alabama, U.S. Data were analyzed using descriptive statistics, and the Chi Square test was used to compare nominal data. A total of 257 participants responded to the survey. Almost 50% of participants had heard of kratom, and 50% had not. Compared to females, males were more likely to have heard of kratom (64% vs. 42%; p = 0.0015), as were pharmacists who worked for an independent pharmacy vs. a chain (61% vs. 41%; p = 0.025). Of the participants who had heard of kratom, only 14% considered themselves knowledgeable or very knowledgeable about the herb, and only 44% knew it was illegal in Alabama. These data indicate a need to further kratom education among community pharmacists in Alabama.

Clinical Pharmacology of the Dietary Supplement Kratom (Mitragyna speciosa).

Kratom (Mitragyna speciosa) consists of over 40 alkaloids, with 2 of them, mitragynine and 7-OH-mitragynine (7-OH-MG) being the main psychoactive compounds. Mitragynine and 7-OH-mitragynine each target opioid receptors and have been referred to as atypical opioids. They exert their pharmacologic effects on the mu, delta, and kappa opioid receptors. In addition, they affect adrenergic, serotonergic, and dopaminergic pathways. Kratom has been touted as an inexpensive, legal alternative to standard opioid replacement therapy such as methadone and buprenorphine. Other uses for kratom include chronic pain, attaining a "legal high," and numerous central nervous system disorders, including anxiety, depression, and posttraumatic stress disorder. Kratom induces analgesia and mild euphoria, with a lower risk of respiratory depression or adverse central nervous system effects compared to traditional opioid medications. Nonetheless, kratom has been associated with both physical and psychological dependence, with some individuals experiencing classic opioid withdrawal symptoms upon abrupt cessation. Kratom use has been linked to serious adverse effects, including liver toxicity, seizures, and death. These risks are often compounded by polysubstance abuse. Further, kratom may potentiate the toxicity of coadministered medications through modulation of cytochrome P450, P-glycoprotein, and uridine diphosphate glucuronosyltransferase enzymes. In 2016, the US Drug Enforcement Administration took steps to classify kratom as a federal schedule 1 medication; however, due to public resistance, this plan was set aside. Until studies are conducted that define kratom's role in treating opioid withdrawal and/or other central nervous system conditions, kratom will likely remain available as a dietary supplement for the foreseeable future.

Midazolam Limited Sampling Strategy With a Population Pharmacokinetic Approach to Simultaneously Estimate Cytochrome P450 (CYP) 3A Constitutive, Inhibition, and Induction/Activation Conditions in Healthy Adults.

We have previously described a midazolam limited sampling strategy employing a population pharmacokinetic (PK) approach to estimate constitutive cytochrome P450 (CYP) 3A activity. This study evaluated expansion of this approach to estimate CYP3A constitutive, inhibitory, and induction activities. Midazolam concentrations (n = 4441) from adults (n = 152) were obtained from previous studies after single, oral, or intravenous administration with intensive sample collection. Data were fit to a 2-compartment population PK model that incorporated CYP3A conditions as covariates for clearance (CL), volume of distribution, and bioavailability (F). Limited sampling models using single- or 2-time point concentrations were compared with full PK profiles using the empiric Bayesian post hoc estimations of midazolam area under the plasma concentration-time curve derived from the population PK model. Ketoconazole, rifampin, and pleconaril were significant covariates of CL, while ketoconazole, rifampin, and grapefruit juice were significant covariates for F. Typical midazolam CL and F estimates were 32.9 L/h and 0.31 for the constituent state, while the ratio of inducer/inhibitor for midazolam CL and CL/F for the induced/inhibited (rifampin/ketoconazole) states were 14.2 and 85.3. Upon comparison to the population PK model, the majority of evaluated single- and 2-time point limited sampling models estimated area under the plasma concentration-time curve had unacceptable r2 and/or unacceptable bias and precision. Exclusively during CYP3A inhibitory conditions, the 4- and 6-hour limited sampling model had acceptable limits of r2 , bias, and precision. Consequently, development of a single- or 2-time point midazolam limited sampling model for general, widespread use to simultaneously evaluate various CYP3A conditions remains elusive.

4ß-Hydroxycholesterol as an Endogenous Biomarker for CYP3A Activity: Literature Review and Critical Evaluation.

A number of cytochrome P450 (CYP)3A phenotyping probes have been used to characterize the drug interaction potential of new molecular entities; of these, midazolam has emerged as the gold standard. Recently, plasma 4ß-hydroxycholesterol (4ß-OHC), the metabolite of CYP3A-mediated cholesterol metabolism, has been championed as an endogenous biomarker for CYP3A, particularly during chronic conditions where CYP3A activity is altered by disease and in long-term treatment studies where midazolam administration is not optimal. Multiple studies in humans have shown that 4ß-OHC can qualitatively differentiate among weak, moderate, and potent CYP3A induction when an inducer, typically rifampin, is administered for up to 2 weeks. Conversely, longer durations of CYP3A inhibitor administration (≥1 month) appear to be necessary to differentiate among weak, moderate, and potent CYP3A inhibitors. A number of studies have reported statistically significant linear relationships between 4ß-OHC plasma concentrations (and 4ß-OHC:cholesterol ratios) and midazolam clearance. However, sufficiently powered studies assessing the ability of 4ß-OHC or 4ß-OHC:cholesterol ratios to measure CYP3A activity (ie, predictive performance) have not been conducted to date. Additional limitations associated with 4ß-OHC phenotyping include inability to detect acute changes in CYP3A activity, uncertainty with regard to its intestinal formation, ambiguity surrounding the role of CYP3A5 in its metabolism, and lack of clarity regarding the role of transporters in its disposition. As such, the data do not support the use of 4ß-OHC or 4ß-OHC:cholesterol ratios as an endogenous biomarker for CYP3A activity.

The Importance of Authentic Leadership to all Generations Represented within Academic Pharmacy.

Academic pharmacy spans several generations including traditionalists, baby boomers, Generation X, and Generation Y, commonly referred to as millennials. It has been suggested that leadership styles must change to accommodate these generational differences in academic pharmacy, yet there are no data of which we are aware, that support this assertion. We contend that leadership styles are derived from one's authentic self and are based on core beliefs and values; therefore, leadership styles must not change to accommodate a specific generation or other subset of academic pharmacy. Instead, effective leaders must change tactics (ie, methods or processes) to reach and influence a specific cohort. This article develops and supports the argument that leadership styles should not change to accommodate generational differences in academic pharmacy.

Correction to: Long-Acting Injectable Second-Generation Antipsychotics: An Update and Comparison Between Agents.

1. In Page 244, under General Pharmacokinetic Principles, Column 1-the following sentence should come after reference 21.

Potential Influence of Centrally Acting Herbal Drugs on Transporters at the Blood-Cerebrospinal Fluid Barrier and Blood-Brain Barrier.

Complementary and alternative medications (CAM) with known or suspected pharmacologic activity in the central nervous system (CNS) are common. These herbal preparations may cause clinically significant drug-drug interactions (DDIs) when coadministered with medications that act in the CNS. This can result in negative outcomes such as toxicity or loss of efficacy. Most drug interaction reports with CAM focus on cytochrome P450 (CYP) modulation. However, drug interactions between CAM and conventional medications may occur via mechanisms other than CYP inhibition or induction; in particular, modulation of drug transport proteins represents an important mechanism by which such interactions may occur. This article provides an updated review of transporter-mediated mechanisms by which herbal products may theoretically interact with centrally acting medications at the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier. Further research is required before the true clinical impact of interactions involving modulation of centrally located membrane transporters can be fully understood.

Stability of isoniazid injection in i.v. solutions.

PURPOSE: Results of an assessment of the chemical stability of isoniazid injection in 0.9% sodium chloride injection and 5% dextrose injection are reported. METHODS: Triplicate solutions of isoniazid (0.5 and 6.0 mg/mL) in the 2 diluents were prepared in ethylene and propylene copolymer i.v. containers and stored under light protection at room temperature (20-25 °C) or under refrigeration (2-8 °C). Standard aliquots were removed from each solution at time points up to 72 hours and analyzed via high-performance liquid chromatography (HPLC). Stability was defined as retention of >90% of the initial isoniazid concentration; pH, osmolality, and visual appearance were assessed. RESULTS: Isoniazid 0.5- and 6.0-mg/mL solutions in 0.9% sodium chloride injection were stable for up to 72 hours at room temperature or under refrigeration. HPLC analysis of isoniazid 0.5-mg/mL solutions in 5% dextrose injection revealed a decrease to less than 90% of the initial concentration at 8 hours at room temperature and at 30 hours under refrigeration. Isoniazid 6.0-mg/mL solutions in 5% dextrose injection were stable for 24 hours at room temperature and for 48 hours under refrigeration. The pH, osmolality, and visual appearance of the solutions were not affected. CONCLUSION: Isoniazid solutions of 0.5 and 6.0 mg/mL in 0.9% sodium chloride injection were stable under light protection for up to 72 hours when stored at room temperature or under refrigeration. Isoniazid injection was less stable in 5% dextrose injection, especially at a concentration of 0.5 mg/mL at room temperature.

Midazolam Single Time Point Concentrations to Estimate Exposure and Cytochrome P450 (CYP) 3A Constitutive Activity Utilizing Limited Sampling Strategy With a Population Pharmacokinetic Approach.

Midazolam is the preferred probe to phenotype cytochrome P450 (CYP) 3A activity. This study evaluated a single-concentration, midazolam limited sampling strategy utilizing a population pharmacokinetic (PK) approach to estimate area under the curve, and thus CYP3A activity. Midazolam concentrations from adults during CYP3A constitutive conditions were obtained from previous studies after single, oral or intravenous administration. Population PK modeling was conducted by nonlinear mixed-effects modeling. Potential covariates of clearance, volume of distribution, and bioavailability were evaluated. A limited sampling model at 1, 2, 4, or 6 hours was selected and fitted with post hoc estimation with the final population PK model. Preset criterion for the limited sampling model selection was a coefficient of determination ≥0.9. Bias and precision were also evaluated. The studies provided 2122 observations from 152 healthy adults. Midazolam concentrations were adequately described by a two-compartment model with first order absorption. Age and sex were significant covariates of central volume (V2 ) and were retained in the final model. An estimate (interindividual variability) of midazolam clearance was 32.5 L/hr (52.9%), covariate of central volume was 67 L (39.1%), and oral bioavailability was 0.33 (45.5%). The final population parameter estimates were within the 95% confidence intervals and were similar to the median bootstrap estimates. Upon comparison to the population PK model, the 4-hour limited sampling model estimated area under the curve had an acceptable coefficient of determination and acceptable bias and precision limits. A 4-hour, but not the 1-, 2-, and 6-hour, single concentration accurately estimated midazolam area under the curve during constitutive CYP3A conditions in healthy adults.

Long-Acting Injectable Second-Generation Antipsychotics: An Update and Comparison Between Agents.

Schizophrenia is a chronic medical condition with periods of remission and relapses over a patient's lifetime. Antipsychotic medications represent the mainstay of treatment for this disease. Long-acting injectable (LAI) formulations of antipsychotics are an attractive alternative to their oral counterparts, as they enhance patient adherence. A number of second-generation antipsychotics (SGAs) are available in LAI formulations. These include paliperidone, aripiprazole, olanzapine, and risperidone. This article reviews the most recently developed and approved of these formulations-aripiprazole monohydrate, aripiprazole lauroxil, and paliperidone palmitate. While all were initially available as once-monthly formulations, a paliperidone palmitate 3-monthly injection formulation has been approved and is the first LAI agent to extend the dosing administration beyond the typical monthly time period. In addition, aripiprazole lauroxil every 6-week and 8-week administration preparations have been developed. LAI preparations of the SGAs have all demonstrated superiority over placebo and are comparable to their oral counterparts in terms of safety and tolerability, if injection site reactions are not taken into account. First-generation antipsychotic LAI preparations (e.g., haloperidol decanoate) have recently been compared with SGA LAI agents, and both formulations demonstrated comparable efficacy with the expected adverse events seen with each drug. Despite their availability, barriers to the use of LAIs remain. Education of both patients and clinicians on the use of LAI formulations and the continued development of these agents are important steps in ensuring these medications are available to the patients they would be most likely to benefit.

Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran.

Dabigatran etexilate (DE) is a P-glycoprotein (P-gp) probe substrate, and its active anticoagulant moiety, dabigatran, is a substrate of the multidrug and toxin extrusion protein-1 (MATE-1) transporter. The antiretroviral pharmacokinetic enhancers, ritonavir and cobicistat, inhibit both these transporters. Healthy volunteers received single doses of DE at 150 mg alone, followed by ritonavir at 100 mg or cobicistat at 150 mg daily for 2 weeks. DE was then given 2 h before ritonavir or cobicistat. One week later, DE was given simultaneously with ritonavir or cobicistat. No significant increases in dabigatran pharmacokinetic (PK) exposure or thrombin time (TT) measures were observed with the simultaneous administration of ritonavir. Separated administration of ritonavir resulted in a mean decrease in dabigatran PK exposure of 29% (90% confidence interval [CI], 18 to 40%) but did not significantly change TT measures. However, cobicistat increased dabigatran PK exposure (area under the concentration-versus-time curve from time zero to infinity and maximum plasma concentration) by 127% each (90% CI, 81 to 173% and 59 to 196%, respectively) and increased TT measures (33% for the area-under-the-effect curve from time zero to 24 h [90% CI, 22 to 44%] and 51% for TT at 24 h [90% CI, 22 to 78%]) when given simultaneously with dabigatran. Similar increases were observed when cobicistat was administered separately by 2 h from the administration of dabigatran. In all comparisons, no significant increase in the dabigatran elimination half-life was observed. Therefore, it is likely safe to coadminister ritonavir with DE, while there is a potential need for reduced dosing and prudent clinical monitoring with the coadministration of cobicistat due to the greater net inhibition of intestinal P-gp transport and increased bioavailability. (This study has been registered at ClinicalTrials.gov under identifier NCT01896622.).

Pharmacokinetic Drug Interactions with Panax ginseng.

Panax ginseng is widely used as an adaptogen throughout the world. The major active constituents of P. ginseng are ginsenosides. Most naturally occurring ginsenosides are deglycosylated by colonic bacteria to intestinal metabolites. Ginsenosides along with these metabolites are widely accepted as being responsible for the pharmacologic activity and drug interaction potential of ginseng. Numerous preclinical studies have assessed the influence of various ginseng components on cytochrome P450 (CYP), glucuronidation, and drug transport activity. Results from these investigations have been largely inconclusive due to the use of different ginseng products and variations in methodology between studies. Drug interaction studies in humans have been conflicting and have largely yielded negative results or results that suggest only a weak interaction. One study using a midazolam probe found weak CYP3A induction and another using a fexofenadine probe found weak P-gp inhibition. Despite several case reports indicating a drug interaction between warfarin and P. ginseng, pharmacokinetic studies involving these agents in combination have failed to find significant pharmacokinetic or pharmacodynamic interactions. To this end, drug interactions involving P. ginseng appear to be rare; however, close clinical monitoring is still suggested for patients taking warfarin or CYP3A or P-gp substrates with narrow therapeutic indices.

Novel in situ self-assembly nanoparticles for formulating a poorly water-soluble drug in oral solid granules, improving stability, palatability, and bioavailability.

PURPOSE: The purpose of this study was to develop a novel lipid-based nanotechnology to formulate poorly water-soluble drugs in oral solid granules to improve stability, palatability, and bioavailability. MATERIALS AND METHODS: In one method, we prepared ritonavir (RTV) nanoparticles (NPs) by a microemulsion-precursor method and then converted the RTV NPs to solid granules by wet granulation to produce RTV NP-containing granules. In the other innovative method, we did not use water in the formulation preparation, and discovered novel in situ self-assembly nanoparticles (ISNPs). We prepared RTV ISNP granules that did not initially contain NPs, but spontaneously produced RTV ISNPs when the granules were introduced to water with gentle agitation. We fully characterized these RTV nanoformulations. We also used rats to test the bioavailability of RTV ISNP granules. Finally, an Astree electronic tongue was used to assess the taste of the RTV ISNP granules. RESULTS: RTV NP-containing granules only had about 1% drug loading of RTV in the solid granules. In contrast, RTV ISNP granules achieved over 16% drug loading and were stable at room temperature over 24 weeks. RTV ISNPs had particle size between 160 nm and 300 nm with narrow size distribution. RTV ISNPs were stable in simulated gastric fluid for 2 hours and in simulated intestinal fluid for another 6 hours. The data from the electronic tongue showed that the RTV ISNP granules were similar in taste to blank ISNP granules, but were much different from RTV solution. RTV ISNP granules increased RTV bioavailability over 2.5-fold compared to RTV solution. CONCLUSION: We successfully discovered and developed novel ISNPs to manufacture RTV ISNP granules that were reconstitutable, stable, and palatable, and improved RTV bioavailability. The novel ISNP nanotechnology is a platform to manufacture oral solid dosage forms for poorly water-soluble drugs, especially for pediatric formulation development.

Part 2 - Coronary angiography with gadofosveset trisodium: a prospective intra-subject comparison for dose optimization for 100 % efficiency imaging.

BACKGROUND: Three tesla (3T) coronary magnetic resonance angiography (MRA) may be optimized using gadolinium-based contrast agents (GBCA) such as gadofosveset trisodium. The goal of this study was to evaluate if there is a qualitative or quantitative improvement in the coronary arteries with variation in contrast dose. METHODS: Twenty-eight healthy volunteers were prospectively recruited for coronary MRA at 3T using a steady state injection technique for 3D radial whole-heart image acquisition with retrospective respiratory self-gating (ClinicalTrials.gov identifier: NCT01853592). Nineteen volunteers completed both single- and double-dose imaging instances (0.03 and 0.06 mmol/kg, respectively). Intra-individual comparison of image quality was assessed by measurement of apparent signal/contrast-to-noise ratio (aSNR/aCNR) and subjective evaluation of image quality by 2 independent reviewers. RESULTS: The average duration of coronary MRA acquisition was 7.2 ± 1.2 min. There was significantly higher (60 %, p < 0.001) aSNR of the aorta and right/left ventricle for the double dose compared to single dose injection scheme and aSNR of the coronary arteries increased by 70 % (p < 0.001) for the double dose injection. aCNR increased by +55 % and +60 % in the ventricles and coronary arteries, respectively (p < 0.001). Overall segmental artery visualization for single dose was possible 47 % of the time, which improved to 60 % with double dose (p = 0.019), predominantly driven by improvements in more distal segment visualization (+40 % improvement in mid arterial segments, p = 0.013). CONCLUSIONS: Gadofosveset trisodium dose of 0.06 mmol/kg significantly quantitatively and qualitatively improves the coronary artery image quality compared to 0.03 mmol/kg at 3T for moderate duration (6-8 min) steady state contrast enhanced coronary MRA.