ACE Inhibitors

Hipertensi adalah suatu penyakit yang tidak menimbulkan gejala (asimptomatik). Menurut (Guytondan Hall, 1997) efek lethal dari hipertensi terutama disebabkan tiga hal berikut : (1) Kelebihan beban kerja pada jantung, yang menimbulkan perkembangan awal dari penyakit jantung kongestif, penyakit jantung koroner, atau keduanya, yang seringkali menyebabkan kematian akibat serangan jantung. (2) Tekanan yang tinggi, yang seringkali menyebabkan rupturnya pembuluh darah utama di otak, yang diikuti oleh kematian pada sebagian besar otak, keadaan ini disebut infark serebral. Secara klinis keadaan ini dikenal dengan nama ‘stroke’. Bergantung pada bagian otak mana yang terkena, stroke dapat menyebabkan kelumpuhan, demensia, kebutaan, atau berbagai 14 gangguan otak yang serius lainnya. (3) Tekanan yang tinggi hampir selalu menyebabkan berbagai pendarahan pada ginjal, yang menimbulkan banyak kerusakan pada area ginjal, dan akhirnya terjadi gagal ginjal, uremia, dan kematian.
Beberapa kelompok obat antihipertensi yaitu diuretic, obat antiadrenergic, vasodilatator antihipertensi, sistem bloker renin-angiotensin-aldosteron, dan antagonis reseptor angiotensin II. Perspektif baru dalam pengobatan hipertensi arterial yaitu dengan mengkombinasikan inhibitor vasodilatasi angiotensin converting enzyme (ACE) dan neutral endopeptidase (NEP) (Kostova, et al. 2005). Dimana  mekanisme kerja ACE-inhibitor (enalapril, lisinopril, captopril dan sebagainya) yaitu dengan menghambat konversi angiotensin I inaktif menjadi angiotensin II yang aktif (vasokonstriktor poten).

Background: In the midst of COVID-19, healthcare specialists and researchers worldwide have been actively investigating treatments for this new disease. As of July 3rd, 2020, there have been a total of 11,048,509 confirmed cases in more than 188 countries and regions with more and more cases being identified every day. Though there have been a couple of medications given EUA status by the FDA such as chloroquine and hydroxychloroquine, remdesivir, and Fresenius Propoven, some of these treatments have been found to carry substantial health risks. Chloroquine and hydroxychloroquine, for example, were found to cause abnormal heart rhythms and facilitated higher rates of death among patients in clinical trials. For this reason, a more natural option such as vitamin D has the potential to be safer and more effective in the prevention of SARS-CoV-2 symptoms.

Objective: In this study, we investigate the benefits of vitamin D supplementation as shown in previous clinical trials involving respiratory illnesses and discussed which foods are most rich in vitamin D. Ultimately, we aim to provide an understanding of the mechanisms by which vitamin D is acquired and the most effective amounts that people should regularly consume in order to strengthen their immune system.
Methods: All of the case studies cited in this review were found through Google Scholar or NCBI by search queries such as “Vitamin D supplementation to treat respiratory illness.” From over 48,000 results, we further searched for clinical trial studies on human subjects which had already been completed. Additional information regarding vaccinations and medications was sourced from the FDA and information about the nutritional value of foods was obtained from the USDA.

Results: Vitamin D has been shown to have many beneficial effects on patients suffering from both respiratory and non-respiratory illnesses. These benefits include, but are not limited to, lowered susceptibility to infection and lower bacterial counts, reduced symptoms of illness, increased serum 25(OH)D, and corrected vitamin D deficiency.

Conclusions: Given the striking symptomatic, molecular, and pathological similarities between infection from SARS-CoV-2 and other respiratory illnesses such as influenza, the positive results from vitamin D supplementation suggest that vitamin D may be a viable prevention option for SARS-CoV-2 symptoms. Through the consumption of vitamin D-rich foods like UV-exposed mushrooms, salmon, and trout, low serum 25(OH)D levels could be corrected, and the reduction of symptoms could be naturally facilitated. Through the induction of cathelicidin and defensin, the regulation of cytokines, and the increased production of anti-microbial peptides, vitamin D has the potential to act as a natural prevention option without adverse side-effects like those caused by chloroquine and other proposed drugs.

Keywords: Vitamin D; Deficiency; Respiratory Illness; COVID-19; Influenza; Cathelicidin; Defensin; SARS-CoV-2; ACE2; ANG II.

Fluorosis, caused by a chronic exposure to fluoride is a worldwide health problem known to affect various organ systems. The present study was aimed at investigating the effect(s) of extracts of seasonal fruits (Indian goose berry, star fruit, guava and wood apple) on angiotensin-converting enzyme (ACE) activity in the lung extracts exposed to different concentrations of fluoride. The lung extracts showed an increasing ACE activity with increasing concentrations of fluoride (2.5-10ppm) with highest ACE activity at 10ppm of fluoride. A reduction in the ACE activity was observed when the fluoride exposed (10ppm) lung extracts were incubated with fruit extracts; wood apple extract exerted a maximum ACE inhibitory activity (28.9%) followed by star fruit, guava and goose berry (20.1 %,19% and 15.5% respectively). A phytochemical analysis and the antioxidant potential of the fruits indicated that the fruits have a high antioxidant potential that correlated well with phytochemical content (phenols, flavonoids, saponins and ascorbic acid) of the fruits. It is suggested that the consumption of these seasonal fruits could be useful in regulating the ACE activity in fluoride endemic areas.

The potential teratogenic effects of Telmisartan were investigated on developing chick embryos.
A dosage of 0.025mL of 1mg/mL of the test agent served as the treatment group while 9% normal saline
solution was introduced to the control group. The test agent was tested on developing chick embryos,
specifically introduced on the 5th day of incubation. Morphological and anatomical abnormalities were
checked and tallied on observation on both stages – embryological development and fully developed and
emerged chicks. The results of this study, specifically tested via scaling by degree of malformations
(qualitative) and Mann Whitney U test (quantitative) at alpha level 0.05 with U = 3 & CV = 5, proved that
the ACE inhibitor drug Telmisartan is significantly teratogenic on developing chick embryos.

Zofenopril is a lipophilic, sulfhydryl group-containing angiotensin-converting enzyme (ACE)-inhibitor, characterized by wide tissue distribution, long duration of action, and pleiotropic effects on endothelial dysfunction. Its clinical efficacy and safety have been described in the four randomized controlled trials of the SMILE program, which globally enrolled more than 3600 patients in post-acute myocardial infarction (AMI) setting. The SMILE-4 study specifically selected patients with left ventricular dysfunction at admission, and compared the effects of zofenopril or ramipril in combination with acetylsalicylic acid (ASA). Zofenopril demonstrated its superiority over ramipril in reducing the combined occurrence of death or hospitalization for cardiovascular causes both in the overall population included in the original study and in subgroups of patients at highest risk, namely hypertensive and diabetic subjects. The effects of the early treatment with zofenopril were sustained over time, and, after 5 years of follow-up, zofenopril increased the survival likelihood and reduced the hospitalization rate. Compared to ramipril, zofenopril was cost-effective with a number to treat of 13 and an incremental cost-effectiveness ratio (ICER) of 2125.45 euros for any additional event prevented. Furthermore, in real-world settings, zofenopril decreased the risk of death in patients with heart failure, particularly in men, and in subjects older than 76 years or with ejection fraction lower than 54%. These results support the early use of zofenopril immediately after AMI, even in the presence of comorbidities, and its maintenance over time to reduce the risk of heart failure.

Angio-oedema and urticaria can be symptoms of both allergic (IgE-mediated) and non-allergic drug hypersensitivity reactions. Non-allergic drug reactions, that may have a similar clinical presentation as allergic drug reactions, are not caused by an IgE-mediated immune mechanism. Because of unfamiliarity with non-allergic drug reactions and the unclear time course between drug use and reactions, the relationship with the responsible drug is often not recognized, leading to unnecessary patient risks. In the present article three patients with angio-oedema and urticaria as side effects of frequently used drugs (ACE-inhibitors, NSAIDs and betalactams) are presented and discussed. Patient A was a 69-year-old man with ACE-inhibitor induced angio-oedema. Patient B was a 40-year-old woman with urticaria and angio-oedema after ingestion of a NSAID caused by a non-allergic drug reaction. Patient C was a 54-year-old woman who developed an anaphylactic shock because of a type I allergy to betalactams.

Cardiovascular events in hypertensives are associated with elevated average blood pressure (BP) and higher short-term BP variability (V), but little is known on treatment effects on BPV and on how to assess changes in short-term BPV. Aim of our study was to address the methodology of short-term BPV assessment and its reduction by Lercanidipine (L) or Enalapril (E) and their combination, through analysis of 24-hour ambulatory BP recordings from two studies including subjects of different age. Study-1: 64 middle-age hypertensives (52.9 ± 9.5 yrs) received L and E s.i.d. at 10 mg (L10, E10) or 20 mg doses (L20, E20) for 8 weeks. Study-2: 66 elderly hypertensives (65.5 ± 4.7 yrs) received placebo, L10, E20 and L10 + E20 s.i.d. for 4 weeks. In middle-age subjects, both L and E decreased mean BP and, at the highest dose, also short-term BPV. In elderly subjects, L10 alone or in combination with E20 reduced BPV. Treatment-induced reductions in BP levels and BPV were uncorrelated. Different methods for short-term BPV assessment did not always provide superimposable results in the elderly. Our study supports a better reduction of BPV by L in the elderly and by E + L combination at any age, suggesting BPV reduction to be independent from reduction in average BP.

BACKGROUND:
In the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) studies, early administration of zofenopril after acute myocardial infarction (AMI) was prognostically beneficial as compared to placebo and other angiotensin-converting enzyme inhibitors (ACEIs), such as lisinopril and ramipril. Here, we investigated whether zofenopril efficacy could be affected by a concomitant use of thiazide diuretics (TDs).
METHODS:
This was a post hoc analysis of pooled individual patient data from the SMILE studies. Patients treated with other diuretics than TDs were excluded. The primary study endpoint was the 1-year combined occurrence of death or hospitalization for CV causes, with or without TD.
RESULTS:
Among 2,995 patients, 263 (8.8%) were treated with a combination including a TD (TD+), whereas 2,732 (91.2%) were not treated with any diuretic (TD-). Proportions of subjects who were treated with TD were equally distributed (p=0.774) within the placebo, zofenopril, and other ACEIs groups. The 1-year risk of major cardiovascular events was similar in TD+ (18.3%) and TD- (16.8%) patients (hazard ratio [HR] 1.04; 95% CI 0.74-1.45; p=0.838). After stratifying per concomitant treatment and TD, the 1-year risk of CV events was significantly lower with zofenopril than with placebo (HR 0.70; 95% CI 0.55-0.88; p=0.002) and other ACEIs (HR 0.58; 95% CI 0.46-0.74; p=0.0001). Treatment with ACEIs and TD as concomitant therapy was associated with a larger blood pressure (BP) reduction (p=0.0001 for systolic BP and p=0.045 for diastolic BP).
CONCLUSION:
In post AMI patients, zofenopril maintained its positive impact on prognosis compared to placebo or other ACEIs, regardless concomitant TD administration. In this setting, TD shows advantages in managing the most difficult hypertensive patients.

BACKGROUND:
Oxidative stress is increased in hyperuricemic patients with acute myocardial infarction (AMI). Use of sulfhydryl ACE-inhibitors (ACEIs), such as zofenopril or captopril, plus xanthine oxidase inhibitors (XOIs), may potentially result in enhanced antioxidant effects and improved survival.
OBJECTIVE:
We verified the benefit of such combination in a randomly stratified sample of 525 of the 3630 post-AMI patients of the four randomized prospective SMILE (Survival of Myocardial Infarction Long-term Evaluation) studies.
METHODS:
One hundred sixty-five (31.4%) patients were treated with XOIs (79 under zofenopril, 86 placebo, lisinopril or ramipril), whereas 360 were not (192 zofenopril, 168 placebo or other ACEIs). In these four groups, we separately estimated the 1-year combined risk of major cardiovascular events (MACE, death or hospitalization for cardiovascular causes).

RESULTS:
MACE occurred in 10.1% of patients receiving zofenopril + XOIs, in 18.6% receiving placebo or other ACEIs + XOIs, in 13.5% receiving zofenopril without XOIs and in 22.0% receiving placebo or other ACEIs, but no XOIs (p = 0.034 across groups). Rate of survival free from MACE was significantly larger under treatment with zofenopril + XOIs than with other ACEIs with no XOIs [hazard ratio: 2.29 (1.06-4.91), p = 0.034]. A non-significant trend for superiority of zofenopril + XOIs combination was observed vs. zofenopril alone [1.19 (0.54-2.64), p = 0.669] or vs. placebo or other ACEIs + XOIs [1.82 (0.78-4.26), p = 0.169].
CONCLUSIONS:
Our retrospective analysis suggests an improved survival free from MACE in post-AMI patients treated with a combination of an urate lowering drug with antioxidant activity and an ACEI, with best effects observed with zofenopril.

Objective: In the four SMILE (Survival of Myocardial Infarction Long-Term Evaluation) studies, early administration of zofenopril in acute myocardial infarction (AMI) showed beneficial effects as compared to placebo and other angiotensin converting enzyme inhibitors (ACEIs). This study investigated whether the concomitant administration of the dihydropyridine calcium channel-blocker amlodipine may improve zofenopril efficacy to prevent cardiovascular events in post-AMI patients. Methods: This was a post-hoc analysis of pooled individual patient data from the four large random-ized SMILE studies. The primary endpoint was the 1-year combined occurrence of death or hospitalization for cardiovascular causes. Results: In total, 3488 patients were considered, 303 (8.7%) treated with concomitant amlodipine. Baseline systolic blood pressure and prevalence of metabolic syndrome were higher in amlodipine treated patients. The 1-year occurrence of major cardiovascular outcomes was significantly reduced in patients receiving concomitant treatment with amlodipine (hazard ratio, HR ¼ 0.66; and 95% confidence interval, CI ¼ 0.44–0.98; p ¼ .039). After accounting for treatment with amlodipine, the risk of cardiovascular events was significantly reduced with zofenopril compared to placebo (HR ¼ 0.78; 95% CI ¼ 0.63–0.97; p ¼ .026]. Among ACEI-treated patients, the zofenopril plus amlodipine combination reduced the risk of cardiovascular events by 38%, compared to the combination of other ACEIs plus amlodipine [HR ¼ 0.76; 95% CI ¼ 0.61–0.94); p ¼ .013). The prognostic benefit of concomitant treatment with zofenopril plus amlodipine was independent from blood pressure lowering. Conclusions: Zofenopril had a positive impact on prognosis in post-AMI patients, compared to other ACEIs. Concomitant administration of amlodipine may help to reduce the risk of cardiovascular events at 1 year.