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Drug-Drug Interactions between Non Steroidal Anti-Inflammatory Drugs (NSAIDs) and Angiotensin Converting Enzyme Inhibitors (ACEIs), Angiotensin Receptor Blocker (ARBs) or diuretics can lead to renal failure and hyperkalemia. Thus, monitoring of serum creatinine and potassium is recommended when a first dispensing of NSAID occur in patients treated with these drugs. We conducted a pharmacoepidemiological retrospective cohort study using data from the French Health Insurance Reimbursement Database to evaluate the proportion of serum creatinine and potassium laboratory monitoring in patients treated with ACEI, ARB or diuretic and receiving a first dispensing of NSAID. We described the first dispensing of NSAID among 3,500 patients of a 4-year cohort (6,633 patients treated with antihypertensive drugs) and analyzed serum creatinine and potassium laboratory monitoring within the 3 weeks after the first NSAID dispensing. General Practitioners were the most frequent prescribers of NSAIDs (85.5%, 95% CI: 84.3-86.6). The more commonly prescribed NSAIDs were ibuprofen (20%), ketoprofen (15%), diclofenac (15%) and piroxicam (12%). Serum creatinine and potassium monitoring was 10.7% (95% CI: 9.5-11.8) in patients treated by ACEIs, ARBs or diuretics. Overall, monitoring was more frequently performed to women aged over 60, treated with digoxin or glucose lowering drugs, but not to patients treated with ACEIs, ARBs or diuretics. Monitoring was more frequent when NSAIDs' prescribers were cardiologists or anesthesiologists. Monitoring of serum creatinine and potassium of patients treated with ACEIs, ARBs or diuretics and receiving a first NSAID dispensing is insufficiently performed and needs to be reinforced through specific interventions.

The apparent shortfall in prevention of coronary heart disease (CHD) noted in early hypertension trials has been attributed to disadvantages of the diuretics and β blockers used. For a given reduction in blood pressure, some suggested that newer agents would confer advantages over diuretics and β blockers. Our aim, therefore, was to compare the effect on non-fatal myocardial infarction and fatal CHD of combinations of atenolol with a thiazide versus amlodipine with perindopril. We did a multicentre, prospective, randomised controlled trial in 19 257 patients with hypertension who were aged 40–79 years and had at least three other cardiovascular risk factors. Patients were assigned either amlodipine 5–10 mg adding perindopril 4–8 mg as required (amlodipine-based regimen; n=9639) or atenolol 50–100 mg adding bendroflumethiazide 1·25–2·5 mg and potassium as required (atenolol-based regimen; n=9618). Our primary endpoint was non-fatal myocardial infarction (including silent myocardial infaction) and fatal CHD. Analysis was by intention to treat. The study was stopped prematurely after 5·5 years' median follow-up and accumulated in total 106 153 patient-years of observation. Though not significant, compared with the atenolol-based regimen, fewer individuals on the amlodipine-based regimen had a primary endpoint (429 vs 474; unadjusted HR 0·90, 95% CI 0·79–1·02, p=0·1052), fatal and non-fatal stroke (327 vs 422; 0·77, 0·66–0·89, p=0·0003), total cardiovascular events and procedures (1362 vs 1602; 0·84, 0·78–0·90, p<0·0001), and all-cause mortality (738 vs 820; 0·89, 0·81–0·99, p=0·025). The incidence of developing diabetes was less on the amlodipine-based regimen (567 vs 799; 0·70, 0·63–0·78, p<0·0001). The amlodipine-based regimen prevented more major cardiovascular events and induced less diabetes than the atenolol-based regimen. On the basis of previous trial evidence, these effects might not be entirely explained by better control of blood pressure, and this issue is addressed in the accompanying article. Nevertheless, the results have implications with respect to optimum combinations of antihypertensive agents.

There is concern that patients taking renin–angiotensin–aldosterone system inhibitors have an increased risk of Covid-19, because angiotensin-converting enzyme 2 is a receptor for the virus. This study showed no increase in likelihood of a positive Covid-19 test or severe Covid-19 in patients taking any of five common classes of antihypertensive drugs.

This population-based case–control study from northern Italy shows that the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 because of a higher prevalence of cardiovascular disease. However, there was no evidence that ACE inhibitors and ARBs affected the risk of Covid-19.

In coronavirus disease 2019 (COVID-19), hypertension and cardiovascular diseases are major risk factors for critical disease progression. However, the underlying causes and the effects of the main anti-hypertensive therapies—angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)—remain unclear. Combining clinical data ( n  = 144) and single-cell sequencing data of airway samples ( n  = 48) with in vitro experiments, we observed a distinct inflammatory predisposition of immune cells in patients with hypertension that correlated with critical COVID-19 progression. ACEI treatment was associated with dampened COVID-19-related hyperinflammation and with increased cell intrinsic antiviral responses, whereas ARB treatment related to enhanced epithelial–immune cell interactions. Macrophages and neutrophils of patients with hypertension, in particular under ARB treatment, exhibited higher expression of the pro-inflammatory cytokines CCL3 and CCL4 and the chemokine receptor CCR1 . Although the limited size of our cohort does not allow us to establish clinical efficacy, our data suggest that the clinical benefits of ACEI treatment in patients with COVID-19 who have hypertension warrant further investigation. Single-cell analysis reveals how anti-hypertensive drugs affect the risk of severe disease in patients with COVID-19 who have hypertension.

Effective delivery of drug carriers selectively to the kidney is challenging because of their uptake by the reticuloendothelial system in the liver and spleen, which limits effective treatment of kidney diseases and results in side effects. To address this issue, we synthesized L-serine (Ser)–modified polyamidoamine dendrimer (PAMAM) as a potent renal targeting drug carrier. Approximately 82% of the dose was accumulated in the kidney at 3 h after i.v. injection of 111In-labeled Ser-PAMAM in mice, while i.v. injection of 111In-labeled unmodified PAMAM, L-threonine modified PAMAM, and L-tyrosine modified PAMAM resulted in kidney accumulations of 28%, 35%, and 31%, respectively. Single-photon emission computed tomography/computed tomography (SPECT/CT) images also indicated that 111In-labeled Ser-PAMAM specifically accumulated in the kidneys. An intrakidney distribution study showed that fluorescein isothiocyanate-labeled Ser-PAMAM accumulated predominantly in renal proximal tubules. Results of a cellular uptake study of Ser-PAMAM in LLC-PK1 cells in the presence of inhibitors [genistein, 5-(N-ethyl-N-isopropyl)amiloride, and lysozyme] revealed that caveolae-mediated endocytosis, micropinocytosis, and megalin were associated with the renal accumulation of Ser-PAMAM. The efficient renal distribution and angiotensin-converting enzyme (ACE) inhibition effect of captopril (CAP), an ACE inhibitor, was observed after i.v. injection of the Ser-PAMAM-CAP conjugate. These findings indicate that Ser-PAMAM is a promising renal targeting drug carrier for the treatment of kidney diseases. Thus, the results of this study demonstrate efficient renal targeting of a drug carrier via Ser modification.

In this trial in persons with chronic kidney disease and type 2 diabetes, combination therapy with finerenone and empagliflozin led to a greater reduction in the urinary albumin-to-creatinine ratio than either drug alone.

Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage. The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101. 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 [13·4%]) and ramipril (1150 [13·5%]; hazard ratio [HR] 1·00, 95% CI 0·92–1·09), but was increased with combination therapy (1233 [14.5%]; HR 1·09, 1·01–1·18, p=0·037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2·21%]) and ramipril (174 [2·03%]; HR 1·09, 0·89–1·34) and more frequent with combination therapy (212 [2·49%]: HR 1·24, 1·01–1·51, p=0·038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (−2·82 [SD 17·2] mL/min/1·73 m 2 vs −4·12 [17·4], p<0·0001) or combination therapy (−6·11 [17·9], p<0·0001). The increase in urinary albumin excretion was less with telmisartan (p=0·004) or with combination therapy (p=0·001) than with ramipril. In people at high vascular risk, telmisartan's effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes. Boehringer-Ingelheim.

ObjectiveTo compare the effect of exercise regimens and medications on systolic blood pressure (SBP).Data sourcesMedline (via PubMed) and the Cochrane Library.Eligibility criteriaRandomised controlled trials (RCTs) of angiotensin-converting enzyme inhibitors (ACE-I), angiotensin-2 receptor blockers (ARBs), β-blockers, calcium channel blockers (CCBs) and diuretics were identified from existing Cochrane reviews. A previously published meta-analysis of exercise interventions was updated to identify recent RCTs that tested the SBP-lowering effects of endurance, dynamic resistance, isometric resistance, and combined endurance and resistance exercise interventions (up to September 2018).DesignRandom-effects network meta-analysis.OutcomeDifference in mean change from baseline SBP between comparator treatments (change from baseline in one group minus that in the other group) and its 95% credible interval (95% CrI), measured in mmHg.ResultsWe included a total of 391 RCTs, 197 of which evaluated exercise interventions (10 461 participants) and 194 evaluated antihypertensive medications (29 281 participants). No RCTs compared directly exercise against medications. While all medication trials included hypertensive populations, only 56 exercise trials included hypertensive participants (≥140 mmHg), corresponding to 3508 individuals. In a 10% random sample, risk of bias was higher in exercise RCTs, primarily due to lack of blinding and incomplete outcome data. In analyses that combined all populations, antihypertensive medications achieved higher reductions in baseline SBP compared with exercise interventions (mean difference −3.96 mmHg, 95% CrI −5.02 to −2.91). Compared with control, all types of exercise (including combination of endurance and resistance) and all classes of antihypertensive medications were effective in lowering baseline SBP. Among hypertensive populations, there were no detectable differences in the SBP-lowering effects of ACE-I, ARB, β-blocker and diuretic medications when compared with endurance or dynamic resistance exercise. There was no detectable inconsistency between direct and indirect comparisons. Although there was evidence of small-study effects, this affected both medication and exercise trials.ConclusionsThe effect of exercise interventions on SBP remains under-studied, especially among hypertensive populations. Our findings confirm modest but consistent reductions in SBP in many studied exercise interventions across all populations but individuals receiving medications generally achieved greater reductions than those following structured exercise regimens. Assuming equally reliable estimates, the SBP-lowering effect of exercise among hypertensive populations appears similar to that of commonly used antihypertensive medications. Generalisability of these findings to real-world clinical settings should be further evaluated.

A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release. The ACE inhibitor captopril was encapsulated into a micelle, which was then embedded into a reversibly thermoresponsive pluronics-based hydrogel matrix. Drug-free and captopril-loaded hydrogels demonstrated excellent product stability and sterility. Rheology testing confirmed sol properties with low viscosity at ambient temperature and increased viscosity and gelation at 37 °C. Captopril-loaded hydrogels significantly inhibited Ang II production in comparison to drug-free hydrogels. DPN mice treated with captopril-loaded hydrogels displayed normalized mechanical sensitivity and reduced inflammation, without side-effects associated with systemic exposure. Our data demonstrate the feasibility of repurposing ACE inhibitors as locally delivered anti-inflammatories for the treatment of sensory deficits in DPN. To the best of our knowledge, this is the first example of a locally delivered ACE inhibitor for the treatment of DPN.