Population pharmacokinetics of lisinopril in hypertensive children and adolescents with normal to mildly reduced kidney function.

AIMS: Lisinopril, an angiotensin-converting enzyme inhibitor, is a frequently prescribed antihypertensive drug in the paediatric population, while being used off-label under the age of 6 years in the USA and for all paediatric patients globally. The SAFEPEDRUG project (IWT-130033) investigated lisinopril pharmacokinetics in hypertensive paediatric patients corresponding with the day-to-day clinical population. METHODS: The dose-escalation pilot study included 13 children with primary and secondary hypertension who received oral lisinopril once daily in the morning; doses ranged from 0.05 to 0.2 mg kg-1 . Patients were aged between 1.9 and 17.9 years (median 13.5 years) and weight ranged between 9.62 and 97.2 kg (median 53.2 kg). All data were analysed using Monolix version 2020R1 (Lixoft, France) and R version 3.6.2. RESULTS: A 1-compartment model with first-order absorption and first-order elimination optimally describes the data. Parameter estimates of absorption rate constant (0.075 h-1 [0.062, 0.088], typical value [95% confidence interval]), volume of distribution (31.38 L 70 kg-1 [10.5, 52.3]) and elimination clearance (24.2 L h-1 70 kg-1 [19.5, 28.9]) show good predictive ability. Significant covariate effects include total body weight on elimination clearance, and distribution volume and estimated glomerular filtration rate (eGFR) on elimination clearance. The effects of eGFR on the elimination clearance are optimally described by a linear effect centred around 105 mL min-1  1.73 m-2 . The effects of body weight were implemented using fixed allometric exponents centred around an adult weight of 70 kg. CONCLUSION: Lisinopril dose and regimen adjustments for paediatric patients should include eGFR on top of weight adjustments. An expanded model characterizing the pharmacodynamic effect is required to identify the optimal dose and dosing regimen.

Oral combined hydrochlorothiazide and lisinopril vs nifedipine for postpartum hypertension: a comparative-effectiveness pilot randomized controlled trial.

BACKGROUND: Angiotensin-converting enzyme inhibitors and diuretics may be underutilized for postpartum hypertension because of their teratogenicity during pregnancy. OBJECTIVE: We evaluated whether combined oral hydrochlorothiazide and lisinopril therapy produced superior short-term blood pressure control when compared with nifedipine among postpartum individuals with hypertension requiring pharmacologic treatment. STUDY DESIGN: We performed a pilot randomized controlled trial (October 2021 to June 2022) that included individuals with chronic hypertension or hypertensive disorders of pregnancy with 2 systolic blood pressure measurements ≥150 mm Hg and/or diastolic blood pressure measurements ≥100 mm Hg within 72 hours after delivery. Participants were randomized to receive either combined hydrochlorothiazide and lisinopril therapy or nifedipine therapy after stratifying the participants by diagnosis (chronic hypertension vs hypertensive disorders of pregnancy). The primary outcome was stage 2 hypertension (systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg) determined using a home blood pressure monitor on days 7 to 10 after delivery or at readmission to the hospital for blood pressure control. The secondary outcomes included severe maternal morbidity (any of the following: intensive care unit admission; hemolysis, elevated liver enzymes, low platelet count syndrome; eclampsia; stroke; cardiomyopathy; or maternal death), need for intravenous medications after randomization, hospital length of stay, blood pressure during first clinic visit, medication compliance, and adverse events. A pilot trial with 70 individuals was planned given the limited available data on combined hydrochlorothiazide and lisinopril therapy use in postpartum care. We calculated relative risks and 95% credible intervals in an intention-to-treat analysis. Finally, we conducted a preplanned Bayesian analysis to estimate the probability of benefit or harm with a neutral informative prior. RESULTS: Of 111 eligible individuals, 70 (63%) agreed and were randomized (31 in the hydrochlorothiazide and lisinopril group and 36 in the nifedipine group; 3 withdrew consent after randomization), and the characteristics were similar at baseline between the groups. The primary outcome was unavailable for 9 (12.8%) participants. The primary outcome occurred in 27% of participants in the hydrochlorothiazide and lisinopril group and in 43% of the participants in the nifedipine group (posterior adjusted relative risk, 0.74; 95% credible interval, 0.40-1.31). Bayesian analysis indicated an 85% posterior probability of a reduction in the primary outcome with combined hydrochlorothiazide and lisinopril therapy relative to nifedipine treatment. No differences were noted in the secondary outcomes or adverse medication events. CONCLUSION: The results of the pilot trial suggest a high probability that combined hydrochlorothiazide and lisinopril therapy produces superior short-term BP control when compared with nifedipine. These findings should be confirmed in a larger trial.

Underreported Risk of Lisinopril-Induced Angioedema in a Veteran Population.

BACKGROUND: Lisinopril-induced angioedema (LIA) is a rare but serious adverse drug event (ADE) with a published incidence of 0.1% to 0.7%. It is well known that ADEs are widely underreported; however, LIA is one of the most reported ADEs within the Veterans Health Administration (VHA). OBJECTIVE: To estimate the effect of underreporting on the risk of LIA within VHA. METHODS: The reported risk of LIA was calculated from reports submitted to the Veterans Affairs (VA) Adverse Drug Event Reporting System (VA ADERS) and the number of veterans prescribed lisinopril. To estimate underreporting, local chart review identified cases of LIA that were compared to reports submitted. The underreporting rate was then applied to the national reported risk. RESULTS: Locally, 68 reports of LIA were submitted of the 21 262 patients prescribed lisinopril, for a reported risk of 0.32%. Nationwide, 14 289 reports of LIA were submitted of the 3 109 661 patients prescribed lisinopril, for a crude reported risk of 0.46%. Of the 324 patients identified for chart review, 240 patients were diagnosed with LIA, suggesting that at least 71.7% of cases were unreported. When this underreporting rate is extrapolated to the national reported risk, a better estimate of the risk of LIA within VHA could increase to 1.6%. CONCLUSION AND RELEVANCE: When estimating the effect of underreporting, the risk of LIA increases to approximately 1.6% or 1 in 63 patients. Because this ADE may affect more patients than previously understood, providers may wish to take LIA into consideration when prescribing lisinopril.

Impact of Lisinopril on Cardiometabolic Risk Factors in Men With Hypertension and Early-onset Androgenetic Alopecia: A Pilot Study.

ABSTRACT: Women with polycystic ovary syndrome are at a high cardiometabolic risk. Early-onset male-pattern baldness is considered the phenotypic equivalent of polycystic ovary syndrome in men. The aim of this study was to assess whether early-onset androgenetic alopecia modifies cardiometabolic effects of lisinopril in men with arterial hypertension. The study population consisted of 62 young men with grade 1 hypertension, 31 of whom were diagnosed with early-onset male-pattern baldness (group A). Thirty-one blood pressure-matched men with normal hair growth (group B) served as a control group. All participants were treated with lisinopril (10-40 mg daily). Blood pressure, glucose homeostasis markers, urinary albumin-to-creatinine ratio (UACR), as well as plasma levels of uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen, homocysteine, total and calculated free testosterone, dehydroepiandrosterone sulfate, and estradiol were assessed before lisinopril treatment and 6 months later. At baseline, levels of all cardiometabolic risk factors were higher in group A than group B. Although lisinopril reduced systolic and diastolic blood pressure, UACR, hsCRP, and fibrinogen in both study groups, these effects were stronger in group B than in group A. Only in group B, the drug decreased levels of uric acid and homocysteine, as well as improved insulin sensitivity. The impact of lisinopril on uric acid, hsCRP, fibrinogen, homocysteine, and UACR correlated weakly with its hypotensive properties, androgen levels, and insulin sensitivity. The obtained results suggest that cardiometabolic effects of lisinopril in men are less pronounced in case of coexisting early-onset androgenetic alopecia.

Tranexamic acid for ACE inhibitor induced angioedema.

Tranexamic acid (TXA) is an antifibrinolytic agent which inhibits conversion of plasminogen to plasmin, a key step in kallikrein activation and bradykinin formation. Tranexamic acid is used in prophylactic management of hereditary angioedema; however, evidence for TXA in angiotensin converting enzyme (ACE) inhibitor-induced angioedema (ACEI-AE) is limited. We describe a patient who presented to the emergency department with ACEI-AE who was successfully treated with TXA. This case suggests that TXA may be a beneficial treatment modality in the management of ACEI-AE and warrants further investigation.

Oral Manifestations of Commonly Prescribed Drugs.

Drugs are being prescribed with more frequency and in higher quantities. A serious adverse drug event from prescribed medications constitutes 2.4% to 16.2% of all hospital admissions. Many of the adverse drug events present intraorally or periorally in isolation or as a clinical symptom of a systemic effect. Clinical recognition and treatment of adverse drug events are important to increase patient adherence, manage drug therapy, or detect early signs of potentially serious outcomes. Oral manifestations of commonly prescribed medications include gingival enlargement, oral hyperpigmentation, oral hypersensitivity reaction, medication-related osteonecrosis, xerostomia, and other oral or perioral conditions. To prevent dose-dependent adverse drug reactions, physicians should prescribe medications judiciously using the lowest effective dose with minimal duration. Alternatively, for oral hypersensitivity reactions that are not dose dependent, quick recognition of clinical symptoms associated with time-dependent drug onset can allow for immediate discontinuation of the medication without discontinuation of other medications. Physicians can manage oral adverse drug events in the office through oral hygiene instructions for gingival enlargement, medication discontinuation for oral pigmentation, and prescription of higher fluoride toothpastes for xerostomia.

C1 esterase inhibitor use in the management of lisinopril-induced angioedema: A case series.

OBJECTIVE: Review 4 patients who presented with presumed lisinopril-induced angioedema and received C1 esterase inhibitor (C1-INH). CASE SUMMARY: Four patients received C1-INH for presumed lisinopril-induced angioedema. In all cases, angioedema was attributed to lisinopril use after the patients' symptoms did not resolve after receiving other interventions. The patients received either 1500 units or 2000 units of C1-INH. All patients' symptoms resolved after receiving a single C1-INH dose, and all were discharged home within 48 hours of receiving C1-INH. PRACTICE IMPLICATIONS: On the basis of the available literature and our study, C1-INH may effectively treat angiotensin-converting enzyme inhibitor-induced angioedema (ACEi-AE). Owing to the low incidence of ACEi-AE and the high cost of C1-INH, physicians should consider limiting the use of C1-INH to patients who remain symptomatic after the initial interventions and are at risk of a compromised airway.

ACE inhibitor-induced angioedema causing small bowel obstruction.

Mucosal angioedema of the face, lips, tongue, and throat is a well-recognized adverse reaction to angiotensin-converting enzyme (ACE) inhibitors that is experienced by a minority of patients. Rarely, this angioedema can involve the small bowel, and patients commonly present with abdominal pain and small bowel obstruction. Due to the increasing number of patients being treated for hypertension, clinicians should consider the diagnosis of small bowel angioedema secondary to ACE inhibitor use in all patients with this presentation who are using this class of medications.

Lisinopril versus lisinopril and losartan for mild childhood IgA nephropathy: a randomized controlled trial (JSKDC01 study).

BACKGROUND: Persistent proteinuria seems to be a risk factor for progression of renal disease. Its reduction by angiotensin-converting inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) is renoprotective. Our previous pilot study showed that 2-year lisinopril therapy is effective and safe for children with mild IgA nephropathy. When combined with ACEI and ARB, reported results are of greater decrease in proteinuria than monotherapy in chronic glomerulonephritis, including IgA nephropathy. To date, however, there have been no randomized controlled trials in children. METHODS: This is an open-label, multicenter, prospective, and randomized phase II controlled trial of 63 children with biopsy-proven proteinuric mild IgA nephropathy. We compared efficacy and safety between patients undergoing lisinopril monotherapy and patients undergoing combination therapy of lisinopril and losartan to determine better treatment for childhood proteinuric mild IgA nephropathy. RESULTS: There was no difference in proteinuria disappearance rate (primary endpoint) between the two groups (cumulative disappearance rate of proteinuria at 24 months: 89.3% vs 89% [combination vs monotherapy]). Moreover, there were no significant differences in side effects between the two groups. CONCLUSIONS: We propose lisinopril monotherapy as treatment for childhood proteinuric mild IgA nephropathy as there are no advantages of combination therapy. CLINICAL TRIAL REGISTRATION: Clinical trial registry, UMIN ID C000000006, https://www.umin.ac.jp .

Lisinopril-associated bullous pemphigoid in an elderly woman: a case report of a rare adverse drug reaction.

An 87-year-old woman with a long-standing history of hypertension, hypothyroidism and diabetes presented to us with scaly and pruritic vesicles of an erythematous base and crusted surface of 2-month duration. They first appeared on her abdomen and gradually spread to her lower back, thighs, before spreading to her upper and lower limbs. Her lesions were non-painful, aggravated by sun exposure only, and sparing mucous membranes. Nikolsky sign was positive with no discernible fluid-filled bullae. History was remarkable only for a doubling of her Lisinopril dosage 2 months prior to the appearance of her lesions, with no other potential environmental and/or drug triggers recognizable on history taking. In light of the appearance of her lesions after her Lisinopril dose escalation, in the absence of any other discernible triggers, an adverse drug reaction (ADR) was entertained, yielding a corresponding Naranjo ADR probability score of 7. Particularly, drug-induced pemphigus foliaceus was initially suspected given her clinical presentation and the morphology and distribution of her lesions. However, her skin biopsy altered our diagnosis to drug-induced bullous pemphigoid (BP) instead, making this the second case reported to date on Lisinopril-induced BP, and the first to report a dose-response variant of this adverse reaction.

Management of persistent lingual angioedema: a team approach.

A 70-year-old African American man suffered anoxic encephalopathy following a choking episode. He had a history of hypertension, which was being treated with lisinopril, an angiotensin-converting enzyme inhibitor (ACEI). Soon after the patient's admission to an intensive care unit, his tongue began to swell until it reached more than twice its normal size and extended almost 2 inches outside his mouth. When the swelling did not diminish after 2 weeks, a diagnosis of ACEI-induced angioedema was determined. ACEIs have the potential to cause angioedema through an uncommon effect on the angiotensin-renin vascular control system. Lingual angioedema can be life-threatening due to the possibility of severe compromise of the airway and thus may require immediate intubation. After the ACEI is discontinued, swelling may remain if there is continued pressure from the maxillary and mandibular incisors on the dorsal and lingual surfaces of the tongue. In this case, the patient was comatose and unable to voluntarily move the tongue; therefore, relief from pressure was easily accomplished, and the edema was eventually diminished through a team effort in which a dentist instructed the nursing personnel on proper placement of Molt mouth props.

Combined angiotensin inhibition for the treatment of diabetic nephropathy.

BACKGROUND: Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

Methods for using clinical laboratory test results as baseline confounders in multi-site observational database studies when missing data are expected.

PURPOSE: Our purpose was to quantify missing baseline laboratory results, assess predictors of missingness, and examine performance of missing data methods. METHODS: Using the Mini-Sentinel Distributed Database from three sites, we selected three exposure-outcome scenarios with laboratory results as baseline confounders. We compared hazard ratios (HRs) or risk differences (RDs) and 95% confidence intervals (CIs) from models that omitted laboratory results, included only available results (complete cases), and included results after applying missing data methods (multiple imputation [MI] regression, MI predictive mean matching [PMM] indicator). RESULTS: Scenario 1 considered glucose among second-generation antipsychotic users and diabetes. Across sites, glucose was available for 27.7-58.9%. Results differed between complete case and missing data models (e.g., olanzapine: HR 0.92 [CI 0.73, 1.12] vs 1.02 [0.90, 1.16]). Across-site models employing different MI approaches provided similar HR and CI; site-specific models provided differing estimates. Scenario 2 evaluated creatinine among individuals starting high versus low dose lisinopril and hyperkalemia. Creatinine availability: 44.5-79.0%. Results differed between complete case and missing data models (e.g., HR 0.84 [CI 0.77, 0.92] vs. 0.88 [0.83, 0.94]). HR and CI were identical across MI methods. Scenario 3 examined international normalized ratio (INR) among warfarin users starting interacting versus noninteracting antimicrobials and bleeding. INR availability: 20.0-92.9%. Results differed between ignoring INR versus including INR using missing data methods (e.g., RD 0.05 [CI -0.03, 0.13] vs 0.09 [0.00, 0.18]). Indicator and PMM methods gave similar estimates. CONCLUSION: Multi-site studies must consider site variability in missing data. Different missing data methods performed similarly. Copyright © 2016 John Wiley & Sons, Ltd.

[Stiffness of the Arterial Wall and Central Hemodynamics During Long-Term Combination Antihypertensive Therapy].

Aim of the METR study - to assess effect of antihypertensive therapy with fixed combination of angiotensin converting enzyme inhibitor lisinopril (10 mg) and calcium antagonist amlodipine (5 mg) on parameters of arterial wall stiffness and central hemodynamics in patients with stage I-II essential hypertension (EH) and functional class II-III ischemic heart disease. Combination therapy was associated with persistent lowering of central arterial pressure, decrease of augmentation index and other parameters of arterial wall stiffness, and reduction of left ventricular myocardial mass. These changes have a potential to lower risk of cardiovascular complications and improve prognosis of patients with EH.

Hypertension in hemodialysis patients treated with atenolol or lisinopril: a randomized controlled trial.

BACKGROUND: The purpose of this study was to determine among maintenance hemodialysis patients with echocardiographic left ventricular hypertrophy and hypertension whether in comparison with a ß-blocker-based antihypertensive therapy, an angiotensin converting enzyme-inhibitor-based antihypertensive therapy causes a greater regression of left ventricular hypertrophy. METHODS: Subjects were randomly assigned to either open-label lisinopril (n = 100) or atenolol (n = 100) each administered three times per week after dialysis. Monthly monitored home blood pressure (BP) was controlled to <140/90 mmHg with medications, dry weight adjustment and sodium restriction. The primary outcome was the change in left ventricular mass index (LVMI) from baseline to 12 months. RESULTS: At baseline, 44-h ambulatory BP was similar in the atenolol (151.5/87.1 mmHg) and lisinopril groups, and improved similarly over time in both groups. However, monthly measured home BP was consistently higher in the lisinopril group despite the need for both a greater number of antihypertensive agents and a greater reduction in dry weight. An independent data safety monitoring board recommended termination because of cardiovascular safety. Serious cardiovascular events in the atenolol group occurred in 16 subjects, who had 20 events, and in the lisinopril group in 28 subjects, who had 43 events {incidence rate ratio (IRR) 2.36 [95% confidence interval (95% CI) 1.36-4.23, P = 0.001]}. Combined serious adverse events of myocardial infarction, stroke and hospitalization for heart failure or cardiovascular death in the atenolol group occurred in 10 subjects, who had 11 events and in the lisinopril group in 17 subjects, who had 23 events (IRR 2.29, P = 0.021). Hospitalizations for heart failure were worse in the lisinopril group (IRR 3.13, P = 0.021). All-cause hospitalizations were higher in the lisinopril group [IRR 1.61 (95% CI 1.18-2.19, P = 0.002)]. LVMI improved with time; no difference between drugs was noted. CONCLUSIONS: Among maintenance dialysis patients with hypertension and left ventricular hypertrophy, atenolol-based antihypertensive therapy may be superior to lisinopril-based therapy in preventing cardiovascular morbidity and all-cause hospitalizations. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number: NCT00582114).

Using semantic predications to uncover drug-drug interactions in clinical data.

In this study we report on potential drug-drug interactions between drugs occurring in patient clinical data. Results are based on relationships in SemMedDB, a database of structured knowledge extracted from all MEDLINE citations (titles and abstracts) using SemRep. The core of our methodology is to construct two potential drug-drug interaction schemas, based on relationships extracted from SemMedDB. In the first schema, Drug1 and Drug2 interact through Drug1's effect on some gene, which in turn affects Drug2. In the second, Drug1 affects Gene1, while Drug2 affects Gene2. Gene1 and Gene2, together, then have an effect on some biological function. After checking each drug pair from the medication lists of each of 22 patients, we found 19 known and 62 unknown drug-drug interactions using both schemas. For example, our results suggest that the interaction of Lisinopril, an ACE inhibitor commonly prescribed for hypertension, and the antidepressant sertraline can potentially increase the likelihood and possibly the severity of psoriasis. We also assessed the relationships extracted by SemRep from a linguistic perspective and found that the precision of SemRep was 0.58 for 300 randomly selected sentences from MEDLINE. Our study demonstrates that the use of structured knowledge in the form of relationships from the biomedical literature can support the discovery of potential drug-drug interactions occurring in patient clinical data. Moreover, SemMedDB provides a good knowledge resource for expanding the range of drugs, genes, and biological functions considered as elements in various drug-drug interaction pathways.

Reversible anuric acute kidney injury secondary to acute renal autoregulatory dysfunction.

Autoregulation of glomerular capillary pressure via regulation of the resistances at the afferent and efferent arterioles plays a critical role in maintaining the glomerular filtration rate over a wide range of mean arterial pressure. Angiotensin II and prostaglandins are among the agents which contribute to autoregulation and drugs which interfere with these agents may have a substantial impact on afferent and efferent arteriolar resistance. We describe a patient who suffered an episode of anuric acute kidney injury following exposure to a nonsteroidal anti-inflammatory agent while on two diuretics, an angiotensin-converting enzyme inhibitor, and an angiotensin receptor blocker. The episode completely resolved and we review some of the mechanisms by which these events may have taken place and suggest the term "acute renal autoregulatory dysfunction" to describe this syndrome.