Tolvaptan: the evidence for its therapeutic value in acute heart failure syndrome

Introduction:

Acute heart failure syndrome (AHFS) is one of the leading causes of hospital admission in the US. Tolvaptan is a vasopressin V₂ receptor antagonist that blocks the effect of arginine vasopressin (AVP) in reabsorbing water from the collecting ducts of the nephrons in congestive heart failure.

Aims:

To review the evidence for utilizing tolvaptan in the treatment of AHFS.

Evidence review:

Several clinical trials have sought to assess the clinical effects of tolvaptan in heart failure. Compared with placebo, tolvaptan has been shown to reduce bodyweight and improve serum sodium in patients with AHFS without worsening renal function. Tolvaptan appeared to be well tolerated with a good safety profile. It caused a significant reduction in pulmonary capillary wedge pressure compared with placebo, but has yet to demonstrate reversal of cardiac remodeling. A large-scale mortality trial showed no differences in long-term mortality rates between tolvaptan and placebo, although early symptom relief was apparent with tolvaptan and lower diuretic use.

Place in therapy:

Tolvaptan has shown to be safe and effective in treating congestion in AHFS. Free water excretion in fluid-overloaded patients vulnerable to cardiorenal compromise with standard diuretic therapy makes V₂ vasopressin receptor blockade an attractive adjunct to standard medical therapy aimed at reducing congestion in AHFS.     

Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non-peptide AVP antagonist in healthy subjects

AIMS

In vitro studies indicated CYP3A4 alone was responsible for tolvaptan metabolism. To determine the effect of a CYP3A4 inhibitor (ketoconazole) and a CYP3A4 inducer (rifampicin) on tolvaptan pharmacokinetics (PK) and pharmacodynamics (PD), two clinical trials were performed.

METHODS

For CYP3A4 inhibition, a double-blind, randomized (5:1), placebo-controlled trial was conducted in 24 healthy subjects given either a single 30 mg dose of tolvaptan (n = 19) or matching placebo (n = 5) on day 1 with a 72 h washout followed by a 3 day regimen of 200 mg ketoconazole, once daily with 30 mg tolvaptan or placebo also given on day 5. For CYP3A4 induction, 14 healthy subjects were given a single dose of 240 mg tolvaptan with 48 h washout followed by a 7 day regimen of 600 mg rifampicin, once daily, with 240 mg tolvaptan also given on the seventh day.

RESULTS

When co-administered with ketoconazole, mean C_max and AUC(0,∞) of tolvaptan were increased 3.48- and 5.40-fold, respectively. Twenty-four hour urine volume increased from 5.9 to 7.7 l. Erythromycin breath testing showed no difference following a single dose of tolvaptan. With rifampicin, tolvaptan mean C_max and AUC were reduced to 0.13- and 0.17-fold of tolvaptan administered alone. Twenty-four hour urine volume decreased from 12.3 to 8.8 l.

CONCLUSIONS

Tolvaptan is a sensitive CYP3A4 substrate with no inhibitory activity. Due to the saturable nature of tolvaptan''s effect on urine excretion rate, changes in the pharmacokinetic profile of tolvaptan do not produce proportional changes in urine output.     

N-Acetylcysteine (NAC)-Induced Hyponatremia Caused by an Electronic Medical Record (EMR) Order Error

Introduction

Intravenous N-acetylcysteine (NAC) causes few adverse drug events, with mild anaphylactoid reactions being the most common. Hyponatremia as a complication of hypoosmolar NAC solution has been reported. We describe how a locally constructed electronic medical record (EMR) order set for IV NAC resulted in a seizure from hyponatremia due to excess free water administration.

Case Report

A 13-month-old female with no past medical history presented to a hospital after ingesting an unknown number of acetaminophen 500 mg tablets. The 4-h acetaminophen concentration was 343 mcg/mL, and she was started on IV NAC. 8.2 h into her 21-h IV NAC protocol, she developed a tonic-clonic seizure. Repeat serum sodium was 124 mEq/L, a decrease from 142 mEq/L at the time of admission. She was treated with hypertonic saline, lorazepam, and levetiracetam and had no further seizures. A brain MRI and EEG were both normal. After the seizure was stabilized, the providers noticed that the patient had receive a total of 900 mL of D5W (112.5 mL/kg) in the first 9 h of hospitalization. This was caused by a poorly constructed, restrictive, EMR order set that did not allow customization of the IV NAC preparation.

Discussion

Because the 21-h IV NAC administration involves preparation of 3 different doses infused over 3 different time intervals, an order set was developed to reduce ordering errors. However, error in its construction caused the pharmacist to prepare a solution containing too much free water, decreasing patient’s intravascular sodium and resulting in a seizure.

Conclusion

The purposes of our case report were to highlight the dangers of overreliance on EMR order sets and to recognize hyponatremic seizures as an adverse reaction of an inappropriately prepared IV NAC.     

Tolvaptan: a new tool for the effective treatment of hyponatremia in psychotic disorders

Importance of the field: Hyponatremia (serum sodium concentration <?136 mEq/liter) is a common and potentially life-threatening medical comorbidity seen in patients with psychotic disorders. Tolvaptan, a selective antagonist of the V₂-receptor, is FDA-approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia. This represents a major development in the care of psychotic individuals with hyponatremia.

Areas covered in the review: This review provides an overview of the existing literature on prevalence rates and risk factors associated with hyponatremia in psychotic patients (1923 – present). Tolvaptan is discussed as a potential advance in the treatment of hyponatremia in patients with psychotic disorders, and preliminary data are reviewed.

What the reader will gain: The reader will gain an appreciation of the prevalence of hyponatremia among psychotic individuals, an understanding of the distinctions between acute and chronic hyponatremia in this population, and awareness that effective treatments are becoming available.

Take home message: A modest literature exists regarding prevalence rates and risk factors associated with hyponatremia in psychotic populations. Hyponatremia is common and serious enough to merit clinical concern. Perhaps, now that tolvaptan has been FDA-approved, progress will accelerate and new insights will develop that begin to bring relief from this medical comorbidity among psychotic patients.     

Assessment of Prophylactic Antibiotic Use in Patients with Surgical Site Infections

Background:

Surgical site infections (SSIs) are the leading cause of hospital-acquired infections and are associated with substantial health care costs, with increased morbidity and death. The Surgical Care Improvement Project (SCIP) contains standards that are nationally reported with the aim of improving patient outcomes after surgery. Our institution’s standards for antimicrobial prophylaxis in the perioperative period are more stringent than these measures and may be considered “beyond SCIP.” The 4 elements of appropriate antimicrobial prophylaxis are timing, antibiotic selection, dosing, and intraoperative redosing.

Objective:

To quantify antimicrobial SSI prophylaxis compliance in accordance with institutional standards and to identify potential opportunities for improvement.

Methods:

Patients aged 18 years or older were included if they had an SSI between January 1, 2009, and June 30, 2010, according to the database maintained prospectively by the Infection Prevention and Control Unit. Adherence to our institution’s practice standards was assessed through analysis of antibiotics administered—timing in relation to the incision, closure, and tourniquet inflation times for the procedure and antibiotic selection, dose, and redosing.

Results:

Overall noncompliance with all 4 elements of antimicrobial prophylaxis was 75.4% among the 760 cases. Repeat dosing had the greatest noncompliance (45.1%); antibiotic selection had the lowest incidence of noncompliance (10.8%).

Conclusions:

Noncompliance existed in each element of antimicrobial SSI prophylaxis, with antibiotic redosing leading in noncompliance. With the implementation of tools to assist the surgical team in following institutional standards, noncompliance will likely decline and additional research opportunities will exist.     

Pharmacokinetics and pharmacodynamics of single-dose oral tolvaptan in fasted and non-fasted states in healthy Caucasian and Japanese male subjects

Purpose

To compare the pharmacokinetics and pharmacodynamics of tolvaptan in Caucasian and Japanese healthy male subjects under fasting and non-fasting conditions.

Methods

This was a single-center, parallel-group, randomized, open-label, three-period crossover trial of single oral doses of tolvaptan 30?mg under fasting and non-fasting [a high-fat, high-calorie meal (HFM) or Japanese standard meal] conditions in 25 healthy male Caucasian subjects and 24 healthy male Japanese subjects. Pharmacodynamic endpoints were urine volume and fluid balance for 0 to 24?h postdose.

Results

In the fasted state, the plasma tolvaptan C_max and AUC_∞ geometric mean ratios (90 % confidence interval) were 1.105 (0.845–1.444) and 1.145 (0.843–1.554) for Japanese compared to Caucasian subjects. A HFM increased the C_max and AUC_∞ values by about 1.15-fold in both Japanese and Caucasian subjects.. Twenty-four-hour urine volumes paralleled pharmacokinetic changes, but the increases were not clinically significant. Fluid balance in the Japanese men was 1.4- to 2.0-fold more negative than that in the Caucasian men.

Conclusion

Tolvaptan pharmacokinetics is not clinically significantly affected by race. Body weight is a factor that affects exposure. Tolvaptan can be administered with or without food.     

Clinical and Financial Impact of Pharmacist Involvement in Discharge Medication Reconciliation at an Academic Medical Center: A Prospective Pilot Study

Background:

Medication reconciliation is one of the more challenging aspects of inpatient care, and its accuracy is paramount to safe transitions of care. Studies have shown that pharmacists have a role in medication reconciliation through improving patient safety and avoiding costs associated with medication errors. The wide-scale use of pharmacists in this process has been limited by time constraints, cost, and lack of resources.

Objective:

This study evaluates the impact of pharmacists in resolving medication errors, decreasing readmission rates, and reducing institutional costs during the discharge medication reconciliation process.

Methods:

Pharmacists evaluated discharge medication reconciliation documentation for patients to determine its accuracy, the accuracy of the admission reconciliation documentation, and any potential issues unrelated to accuracy. Analysis of these data determined the time required for pharmacist involvement, the number of errors identified by pharmacists, the quality of pharmacist interventions, the cost avoidance for each error, and the overall impact on hospital readmission.

Results:

During the 7-week study period, pharmacists performed 67 discharge medication reviews and identified 84 errors. Seventy-five percent were considered to be significant and 6% were considered to be serious. The 30-day readmission rate in the study cohort was 18% compared with 20% in the control group. Based on the clinical severity scale and pharmacist salaries, pharmacist interventions resulted in $42,300 in cost avoidance.

Conclusion:

Pharmacists involved in this pilot discharge process identified and resolved significant errors on medication reconciliation orders that resulted in a financial benefit to the institution.     

Effect of grapefruit juice on the pharmacokinetics of tolvaptan,a non-peptide arginine vasopressin antagonist,in healthy subjects

Purpose  

Tolvaptan is a selective vasopressin V2 receptor antagonist that can be given orally once daily for treatment of clinically significant hypervolemic and euvolemic hyponatremia (US and Europe) or extracellular volume expansion despite taking other diuretics (Japan). In vitro studies indicated that tolvaptan was a CYP3A4 substrate.     

Pharmacy students' perceptions of a required senior research project

Objectives

To determine pharmacy students'' perceptions of a required research project in a doctor of pharmacy curriculum.

Methods

A survey instrument was administered to senior pharmacy students to determine their perceptions of the project advisor and overall project experience and their postgraduation employment plans.

Results

Two-hundred twenty-nine (81.5%) students completed a survey instrument. The majority agreed or strongly agreed that the project provided a valuable learning experience (88.2%), provided a competitive advantage for postgraduate job opportunities (73.2%), and should be a continued graduation requirement (74.2%). Respondents with plans for a residency or fellowship were more likely than those entering a community or hospital/institutional pharmacy to agree that completion of the project made them more qualified or marketable and should be continued as a graduation requirement (p < 0.05).

Conclusions

A required research project was perceived by pharmacy students to be a beneficial experience. Students pursuing residency or fellowship were more likely to feel the project was beneficial than students entering the workforce.     

Novel gastroretentive sustained-release tablet of tacrolimus based on self-microemulsifying mixture: in vitro evaluation and in vivo bioavailability test

Aim:

To develop a novel gastroretentive drug delivery system based on a self-microemulsifying (SME) lipid mixture for improving the oral absorption of the immunosuppressant tacrolimus.

Methods:

Liquid SME mixture, composed of Cremophor RH40 and monocaprylin glycerate, was blended with polyethylene oxide, chitosan, polyvinylpyrrolidone and mannitol, and then transformed into tablets via granulation, with ethanol as the wetting agent. The tablets were characterized in respect of swelling, bioadhesive and SME properties. In vitro dissolution was conducted using an HCl buffer at pH 1.2. Oral bioavailability of the tablets was examined in fasted beagle dogs.

Results:

The tablet could expand to 13.5 mm in diameter and 15 mm in thickness during the initial 20 min of contact with the HCl buffer at pH 1.2. The bioadhesive strength was as high as 0.98±0.06 N/cm². The SME gastroretentive sustained-release tablets preserved the SME capability of the liquid SME formations under transmission electron microscope. The drug-release curve was fit to the zero-order release model, which was helpful in reducing fluctuations in blood concentration. Compared with the commercially available capsules of tacrolimus, the relative bioavailability of the SME gastroretentive sustained-release tablets was 553.4%±353.8%.

Conclusion:

SME gastroretentive sustained-release tablets can enhance the oral bioavailability of tacrolimus with poor solubility and a narrow absorption window.     

Learning outcomes and program-level evaluation in a four-year undergraduate pharmacy curriculum

Objective

To determine the successful implementation and effectiveness of program-level learning outcomes for a 4-year bachelor of science pharmacy degree program.

Methods

A comprehensive and iterative program evaluation framework was implemented and quantitative and qualitative data were gathered.

Results

The critical factors in the successful development and implementation of program-level learning outcomes in this context were program accreditation, the leadership qualities of the curriculum chair, a strong and adequately resourced curriculum team that was able to engage and mobilize the faculty learning community, and scholarly approaches to curriculum reform.

Conclusion

An integrated range of institutional and programmatic strategies enhance the implementation of program-level learning outcomes in a 4-year undergraduate curriculum.     

Prevalence and treatment of isolated and concurrent hypertension and hypercholesterolaemia in the United Kingdom

AIMS

To determine the prevalence and treatment of hypertension, dyslipidaemia and both together in the UK between 1998 and 2006.

METHODS

We used The Health Improvement Network (THIN) a general practice-based database from 1998 to 2006 and we compared the 1998 and 2003 data to that taken from the Health Survey for England (HSE) in 1998 and 2003.

RESULTS

The prevalence (treatment) of hypertension was 25.3% (11.4%) in 1998, 27.8% (15.1%) in 2003 and 26.9% (16.2%) in 2006 in THIN. In HSE it was 37.3% (9.6%) in 1998 and 32.9% (13.8%) in 2003. For dyslipidaemia the figures were 8.6% (1.9%), 18.5% (6.5%) and 24.4% (9.8%) for THIN and 67.8% (2.3%) and 74.9% (7.0%) for HSE. Concurrent hypertension and dyslipidaemia in THIN increased from 5.5% (1.1%) in 1998 to 13.5% (4.5%) in 2003 and 17.4% (7.1%) in 2006. The prevalence of both conditions was 30.6% (0.7%) in HSE in 1998 and 28.7% (3.1%) in 2003.

CONCLUSIONS

There has been a progressive improvement in the detection and treatment of hypertension, dyslipidaemia and both conditions together between 1998 and 2006. However, much still needs to be done to improve the diagnosis and treatment of hypertension, hypercholesterolaemia and concurrent hypertension and hypercholesterolaemia in the United Kingdom.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The 1998 and 2003 Health Survey for England revealed a high prevalence of hypertension and hypercholesterolaemia in the population of England.
• Major changes in the reimbursement of primary care for the management of both hypertension and hypercholesterolaemia have occurred in the UK.

WHAT THIS STUDY ADDS

• Using a GP database we have examined the proportion of subjects diagnosed and treated for hypertension and hypercholesterolaemia over time. To examine the true population rates and primary care data we compared the results of the Health survey for England in both 1998 and 2003 with the recorded data on GP computers.
• Despite current guidelines, many patients with hypertension and/or hypercholesterolaemia are under-treated and, even amongst those who are treated, many do not achieve their blood pressure and/or lipid targets.
• Although treatment rates in the UK have improved recently, particularly for lipid-lowering therapies, they remain suboptimal.

     

Effects of tight versus non tight control of metabolic acidosis on early renal function after kidney transplantation

Background

Recently, several studies have been conducted to determine the optimal strategy for intra-operative fluid replacement therapy in renal transplantation surgery. Since infusion of sodium bicarbonate as a buffer seems to be safer than other buffer compounds (lactate, gluconate, acetate)that indirectly convert into it within the liver, We hypothesized tight control of metabolic acidosis by infusion of sodium bicarbonate may improve early post-operative renal function in renal transplant recipients.

Methods

120 patients were randomly divided into two equal groups. In group A, bicarbonate was infused intra-operatively according to Base Excess (BE) measurements to achieve the normal values of BE (−5 to +5 mEq/L). In group B, infusion of bicarbonate was allowed only in case of severe metabolic acidosis (BE ≤ −15 mEq/L or bicarbonate ≤ 10 mEq/L or PH ≤ 7.15). Minute ventilation was adjusted to keep PaCO₂ within the normal range. Primary end-point was sampling of serum creatinine level in first, second, third and seventh post-operative days for statistical comparison between groups. Secondary objectives were comparison of cumulative urine volumes in the first 24 h of post-operative period and serum BUN levels which were obtained in first, second, third and seventh post-operative days.

Results

In group A, all of consecutive serum creatinine levels were significantly lower in comparison with group B. With regard to secondary outcomes, no significant difference between groups was observed.

Conclusion

Intra-operative tight control of metabolic acidosis by infusion of Sodium Bicarbonate in renal transplant recipients may improve early post-operative renal function.     

The effect of selective serotonin re-uptake inhibitors on the risk of myocardial infarction in a cohort of patients with depression

AIM

To evaluate whether selective serotonin re-uptake inhibitor (SSRI) exposure influences the risk of myocardial infarction (MI) in patients with depression.

METHODS

This study included 693 patients with MI (cases) and 2772 controls. Conditional logistic regression was used to calculate the odds ratio (OR).

RESULTS

SSRI exposure may be associated with a reduced MI risk (OR = 0.77, 95% CI 0.57, 1.03). However, reduced risk was only observed with longer term use (OR = 0.73, 95% CI 0.53, 1.00) and not with shorter term use (OR = 1.15, 95% CI: 0.65, 2.05).

CONCLUSIONS

Only longer term use of SSRIs was associated with reduced MI risk, suggesting that other mechanisms, besides an acute anti-platelet effect, may reduce MI risk.     

Blood Urea Nitrogen/Creatinine Ratio and Response to Tolvaptan in Patients with Decompensated Heart Failure: A Retrospective Analysis

Introduction

Arginine vasopressin-stimulated reabsorption of urea occurs in the collecting duct via increased expression of the urea transporter.

Objective

The aim of this study was to evaluate whether the blood urea nitrogen/creatinine (BUN/Cr) ratio is useful for predicting tolvaptan response in patients with decompensated heart failure (HF).

Methods

Among 71 consecutive patients with HF who received oral tolvaptan between 2010 and 2014, we retrospectively studied 33 patients with decompensated HF without any mechanical circulatory assistance or inotropic support who had already been treated with loop diuretics. A responder to tolvaptan was defined as an individual who experienced a ≥30 % increase in their respective 24-h urine volume.

Results

Among the 33 patients, 21 met the criteria of a responder. The area under the receiver operating characteristic curves of BUN/Cr and BUN were 0.790 and 0.714, respectively, and the respective cut-off values for responders to tolvaptan were 23.8 and 49.0. BUN/Cr and BUN retained their significant relationships with the responder status (odds ratio for BUN/Cr >23.8: 20.9; 95 % confidence interval [CI] 2.7–531.1; p = 0.002; odds ratio for BUN ≥49: 7.7; 95 % CI 1.4–65.8; p = 0.02).

Conclusion

Our results suggest that high BUN/Cr may be a predictor of response to tolvaptan in decompensated HF patients. A prospective study with a large sample size is required to confirm this preliminary finding.

     

Sustained-Release Fampridine (4-Aminopyridine) in Multiple Sclerosis: Efficacy and Impact on Motor Function

Objective

The aim of this study was to determine the efficacy of sustained-release fampridine (4-aminopyridine) in veterans with multiple sclerosis (MS) with limited ambulatory ability, and its impact on motor function in an outpatient setting.

Design

Retrospective.

Setting

Tertiary referral center [Veterans Affairs (VA) Medical Center].

Participants

Veterans; 20 MS patients were prescribed dalfampridine (10 mg twice daily) due to their difficulty with walking based on patient and caregiver report and clinician impression of change in the ability to ambulate based on prior 10-meter (10M) and 2-minute walk tests (2MWTs).

Intervention

Not applicable.

Main Outcome Measures

The primary outcome measures were mean changes in walking speed (10M walk test), walking distance (2MWT), and Total Functional Independence Measure (TFIM). Improvement of >20 % in walking speed was indicated as a clinically meaningful change.

Results

Treatment with dalfampridine resulted in significant improvement in walking speed and endurance (p < 0.05). Walking speed increased by 33 % and walking endurance by 31 %, representing clinically meaningful improvement. This change was not influenced by change in muscle tone. This improvement in mobility was associated with a clinically significant change in motor function. Adverse effects, including insomnia, dizziness, and headache, were experienced by five patients who discontinued the medication after a minimum of 4 weeks.

Conclusion

Treatment with dalfampridine resulted in clinically relevant improvements in walking speed and endurance in MS patients with limited ambulation and helped improve their motor function.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-013-0020-x) contains supplementary material, which is available to authorized users.     

Heterogeneity of chemosensitivity in esophageal cancer using ATP-tumor chemosensitivity assay

Aim:

Current chemotherapy for esophageal cancer is conducted on the basis of empirical information from clinical trials, which fails to take into account the known heterogeneity of chemosensitivity between patients. This study was aimed to demonstrate the degree of heterogeneity of chemosensitivity in esophageal cancers.

Methods:

A total of 42 esophageal cancer specimens were collected. The heterogeneity of chemosensitivity in esophageal cancer specimens was examined using an ex vivo ATP-tumor chemosensitivity assay (ATP-TCA).

Results:

Thirty eight specimens produced evaluable results (90.5%). The most active single agent tested was nedaplatin, to which 28.9% of samples were sensitive. Combinations of chemotherapy agents exhibited much higher sensitivity: cisplatin+paclitaxel was sensitive in 16 of 38 (42.1%) of samples, while nedaplatin+paclitaxel was more effective, which was sensitive in 20 of 38 cases (52.6%).

Conclusion:

There was a marked heterogeneity of chemosensitivity in esophageal cancer. Chemosensitivity testing may provide a practical method for testing new regimens before clinical trials in esophageal cancer patients.     

Low prevalence of hyponatremia codification in departments of internal medicine and its prognostic implications

Abstract

Objective:

Hyponatremia is the most frequent ionic disorder among ambulatory and hospitalized populations. The aim of the study is to describe the profile of patients admitted to internal medicine departments of Spanish hospitals with a diagnostic codification of hyponatremia in their discharge sheets.