Subcutaneous furosemide for the treatment of heart failure: a state-of-the art review.

The prevalence of heart failure (HF) is on the rise. By 2030, over eight million Americans (46% increase from current prevalence) will have heart failure. In the USA, approximately 30 billion dollars is spent annually on heart failure and this number will likely double in 2030. Thus, HF represents a significant economic burden. Acute decompensated heart failure (ADHF) is a clinical spectrum, which refers to increasing symptoms and signs of heart failure prompting an emergency room visit or hospitalization. In ADHF, inpatient administration of intravenous diuretic is the standard of care due to the variability in the absorption of oral diuretics. Within 30 days, 25-30% of these patients are readmitted with recurrent ADHF. Recent efforts have focused in reducing HF readmission, and thereby decreasing costs; hence, innovative outpatient treatment options have emerged. Subcutaneous furosemide use will potentially overcome the need to place intravenous lines, reduce associated expenses, and enable management of ADHF at home. This review presents data on the pharmacodynamics and pharmacokinetics of subcutaneous furosemide, scientific evidence on the use of this therapy in the palliative and hospice population, and its experimental use as an outpatient therapy and/or as a bridge from inpatient to home.

Acute kidney injury secondary to a combination of renin-angiotensin system inhibitors, diuretics and NSAIDS: "The Triple Whammy".

BACKGROUND: Renin-angiotensin system inhibitors (ACEI/ARB-II), diuretics and NSAIDs, a combination known as "Triple Whammy", can result in decreased glomerular filtration rate (GFR) and acute kidney injury (AKI). Objectives: To describe the incidence of AKI for each drug type and their combinations. To define the profile of patients admitted for drug-related AKI secondary to Triple Whammy drugs (AKITW), with an assessment of costs and mortality. METHODS: A retrospective observational 15-month study developed in three stages: - First: a cross-sectional stage to identify and describe hospitalizations due to AKITW. - Second: a follow-up stage of an outpatient cohort consuming these drugs (15,307 subjects). - Third: a cohort stage to assess costs and mortality, which compared 62 hospitalized patients with AKITW and 62 without AKI, paired by medical specialty, sex, age and comorbidity according to their Clinical Risk Groups. RESULTS: There were 85 hospitalization episodes due to AKITW, and 78% of patients were over the age of 70. The incidence of AKITW in the population was 3.40 cases/1000 users/year (95% CI: 2.59-4.45). By categories, these were: NSAIDs + diuretics 8.99 (95% CI: 3.16-25.3); Triple Whammy 8.82 (95% CI: 4.4-17.3); ACEI/ARB-II + diuretics 6.87 (95% CI: 4.81-9.82); and monotherapy with diuretics 3.31 (95% CI: 1.39-7.85). Mean hospital stay was 7.6 days (SD 6.4), and mean avoidable costs were estimated at €214,604/100,000 inhabitants/year. Mortality during hospitalization and at 12 months was 11.3% and 38.7% respectively, and there were no significant differences when compared with the control group. CONCLUSIONS: Treatment with ACEI, ARB-II, diuretics and/or NSAIDs shows a high incidence of hospitalization episodes due to AKI; diuretics as monotherapy or dual and triple combination therapy cause the highest incidence. AKITW involves high health care costs and avoidable mortality.

Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.

In vivo assessment of novel furosemide gastro-mucoadhesive delivery system based on a kind of anion ion-exchange fiber.

A novel gastro-mucoadhesive delivery system based on a kind of anion ion-exchange fiber has been developed. Furosemide (FM), which is site-specifically absorbed from the upper gastrointestinal (GI) tract, was used as model drug. A novel-modified dissolution system, which can also be called "flow through diffusion cell," was used to study the drug release from the drug fibers. The GI transit studies of the FM fiber complexes in rats and gamma imaging studies in volunteers were carried out to evaluate the gastro-mucoadhesive behavior of the fiber. The pharmacokinetic profile and parameters of the FM suspension and FM fiber in fasted and fed rats were measured, respectively. Studies on rats and volunteers provided evidence for the validity of the hypothesis that the drug fiber provided better gastro-mucoadhesive properties in vivo.

Bioequivalence assessment of two formulations of spironolactone in Chinese healthy male volunteers.

The bioavailability of a new spironolactone ((7alpha,17alpha)-7-(acetylthio)-17-hydroxy-3-oxopregn-4-ene-21-carboxylic acid gamma-lactone, CAS 52-01-7) formulation (test) was compared with a commercially available original formulation (reference) of the drug in 20 Chinese healthy male volunteers, aged between 21 and 27. The trial was designed as an open, randomized, single blind two-sequence, two-period crossover study. Under fasting conditions, each subject received a single oral dose of 100 mg spironolactone as a test or reference formulation with a 7-day washout period between the two formulations. The plasma concentrations of spironolactone and its active metabolite canrenone (CAS 976-71-6) were analyzed by a sensitive liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (LC-APCI-MS) method. The pharmacokinetic parameters included AUC(0.t), AUC(0-infinity), C(max), t1/2, and T(max). Values of AUC(0-t) demonstrate nearly identical bioavailability of spironolactone from the examined formulations. The AUC(0.12) of spironolactone was 148.35 +/- 39.5 and 144.39 +/- 53.02 ng x h/ml for the test and reference formulation, respectively. The AUC(0-60) of the metabolite canrenone was 1873.36 +/- 318.10 and 1911.28 +/- 355.60 ng h/ml for test and reference formulation, respectively. The maximum plasma concentration (C(max)) of spironolactone was 48.34 +/- 21.16 ng/ml for the test and 47.40 +/- 23.40 ng/ml for the reference product and the C(max) of the metabolite was 122.90 +/- 27.70 and 123.35 +/- 27.29 ng/ml for the test and reference product, respectively. No statistical differences were observed for C(max) and the area under the plasma concentration-time curve for both spironolactone and its active metabolite canrenone. 90% confidence limits calculated for C(max) and AUC from zero to infinity (AUC(0-infinity)) of spironolactone and its metabolite were included in the bioequivalence range (80%-125% for AUC). This study shows that the test formulation is bioequivalent to the reference formulation for spironolactone and its main active metabolite canrenone.

Studies on the metabolic fate of M17055, a novel diuretic (6). Assessment for drug-drug interactions of M17055 in metabolism, distribution and excretion.

1. The potential of M17055, a novel diuretic candidate, to affect the activities of human CYP enzymes, alter the plasma unbound fraction and compete with concomitant drugs in renal secretion as part of an assessment for drug-drug interactions in metabolism, distribution and excretion was investigated. 2. The effects of M17055 on the activities of human CYP1A2, CYP2E1, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 were considered negligible at clinically relevant concentrations. 3. The majority of M17055 (99%) was bound to human plasma proteins, but it is unlikely to alter the binding of other clinically relevant drugs. 4. The renal clearance of M17055 (corrected for the plasma unbound fraction in male rats) substantially exceeded the glomerular filtration rate and was markedly reduced by treatment with probenecid, suggesting that the renal excretion of M17055 is controlled predominantly by an active secretion mechanism. 5. The results show that M17055 is unlikely to cause or undergo significant pharmacokinetic interactions with concomitant drugs in metabolism and distribution. However, when it is administered simultaneously with certain organic anions, drug-drug interactions during kidney excretion may be possible.

Statistical evaluation of the regulatory guidelines for use of furosemide in race horses.

The pharmacokinetic behavior of furosemide concentrations in performance horses is of great interest to the equine industry and equine researchers. Specifically, such information is useful for the evaluation of the existing guidelines in several racing jurisdictions and for the possible development of new guidelines for varying time periods after administration. We studied several approaches within the framework of nonlinear mixed effects models to increase the accuracy of evaluating these guidelines. Theoretical properties of the proposed methods were examined and the variances of the resulting estimators compared. Their numerical performances were further evaluated through simulations. Finally, we applied these methods to a furosemide concentration profile data set and used our findings to address certain important practical issues.

Assessment of pharmaceutical quality of furosemide tablets from multinational markets.

This report describes results of a collaborative study in which samples of the 40-mg strength of furosemide tablets were evaluated following a common protocol based on British (BP), European (Ph. Eur.), and US Pharmacopoeial (USP) specifications. Several tests, including identification, uniformity of mass, and dissolution, were performed. In total, excluding Lasix lots, results for 162 lots obtained from 115 manufacturers or suppliers were submitted. Also, 23 laboratories identified and submitted data for 34 lots of Lasix products available in their countries. There were no reported abnormalities in the physical test requirements of the products analyzed. The summaries (n, mean, and 95% CI) of the assay results for the "standard sample" (a common sample), Lasix lots from participating countries, and for all other furosemide products, respectively, are as follows: 30, 99.8%, 96-104; 33, 100.0%, 94-106; and 162, 99.6, 94-105. About half (approximately 62%) of the reported uniformity of mass results based on tablet weights were in the range 150-175 mg/tablet. However, there appears to be notable variability in tablet weights that would result in significant differences in the ratios (0.14 to 0.40) of active ingredient to excipient. The reported disintegration times ranged from 0 (instantaneous) to 18 min, with most less than 1 min. The drug dissolution testing was conducted with phosphate buffer at pH 5.8 (USP recommended). Another test was conducted with acetate buffer at pH 4.6 (noncompendial). There appears to be remarkable similarity in overall percentage of drug release from the three types of products (standard sample, Lasix lots, and other products). Although apparently there is a very wide spread in dissolution characteristics of the products tested, the analyses of variance did not detect differences among the products tested and, to this extent, would not indicate differences in bioavailability characteristics for most of these products. It is observed that about 20-38% of the variability in dissolution testing is not product related (i.e., it is from the dissolution testing itself), while the remaining 62-80% variability is product related (manufacturing, formulation, etc). The results of this multinational collaborative study showed that most of the furosemide products available in different countries met the required pharmaceutical quality standards, including drug-release characteristics. Based on an extensive statistical analysis, the main concern from the study was that the high variability in drug dissolution testing would require wide tolerance standards (e.g., pharmacopoeial standards). This may result in lack of needed discriminating ability of the test in revealing the impacts of formulation and manufacturing changes on in vitro, and perhaps in vivo, drug-release characteristics.

[Assessment of the role of enterocyte ion exchange in the intestinal absorption of amoxicillin, based on a study of the interaction with amiloride]. / Evaluation du rôle des échanges ioniques entérocytaires dans l'absorption intestinale de l'amoxicilline par l'étude de l'interaction avec l'amiloride.

Intestinal dipeptide carrier system has been shown in vitro to be involved in intestinal absorption of betalactam antibiotics. Given that efficiency of this transport system depends on a pH gradient (extracellular pH < intracellular pH) at the brush-border membrane of enterocytes, we assessed the effects of amiloride, a known inhibitor of the Na-H exchange, on the bioavilability of oral amoxicillin in eight normal volunteers. Following a single 10 mg oral dose of amiloride, the absolute bioavailability of oral amoxicillin turned out to decrease by 27% (p < 0.01). The extent of reduction of oral amoxicillin AUC appeared to significantly correlate (p = 0.005) with the extent of decrease in potassium renal excretion but not with variations in antibiotic renal clearance under amiloride effect. Such patterns seem to confirm in vivo the role of the Na-H exchange in betalactam absorption and to suggest the underlying regulatory function of intracellular Na concentration, the latter depending on the (NaK)-ATPase activity.