The pathogenesis of cutaneous tumors has been known for decades yet remains largely unexplained or incompletely understood. The reason for this mystery lies in the concepts of photosensitivity and phototoxicity: how do they arise or what actually causes them? Recently published data in the medical literature link certain nitrosamines such as nitrosomorpholine, for example, to gene and phototoxicity in humans. A number of other nitrosamines analogous in action and structure are found as contaminants in about 300 of the most widely distributed pharmaceuticals worldwide: NDEA, NDMA, NMBA and many others. These contaminated drugs include beta blockers/ bisoprolol/, thiazide diuretics/ hydrochlorothiazide/, antiarrhythmics/ propafenone/, ACE inhibitors/ lisinopril/, but also a number of other drugs which are, according to the FDA, found to have contaminants with a certain carcinogenic potency ranging between 1 and 5. The phototoxicity and genotoxicity of these contaminants, attributed to the pathogenesis of skin tumors, still remain a mystery. The problems of the intake of the above-mentioned groups of drugs arise mainly on the basis of the official bulletins of the regulatory bodies, namely that: in practice, the intake of polymedication could in many cases also be considered as regular, permanent, long-term intake of contaminants/carcinogens/mutagens of heterogeneous type, also known as nitrosamines or NDSRIs. Nitrosamines are genome modifiers in humans and cause acquired mutations. Their concomitant administration in the context of standard, but currently not yet officially declared as contaminated polymedication, would be able to block certain tumor suppressor genes (p53) as well as activate RAS oncogenes. Or in practice- daily administration of a particular combination of drugs could activate the cascades of carcinogenesis regulating the genesis of skin cancer. Precisely because of this fact, it should not be surprising to anyone that the concurrent intake of the aforementioned drugs could also be associated with the clinical manifestation of multiple keratinocytic tumors. We describe a consecutive case of a patient who developed 4 keratinocytic tumors: 2 basal cell carcinomas, 1 keratoacanthoma, and 1 squamous cell carcinoma on a background of potentially contaminated polymedication with propafenone, lisinopril, hydrochlorothiazide, and bisoprolol. Recently published innovative international data on the topic are discussed in the context of concepts such as drug-mediated nitrosogenesis, photonitrosо-carcinogenesis and metabolic programming/ reprogramming of the tumor cell.

Objectives: This systematic review and meta-analysis aimed to assess the blood pressure (BP)-lowering effect and the safety profile of low-dose bisoprolol/hydrochlorothiazide combination treatment in patients with hypertension. Methods: Multiple electronic databases were systematically searched, and five clinical studies were included in the meta-analysis. Results: Treatment with bisoprolol/hydrochlorothiazide significantly reduced systolic BP (SBP) [mean difference (MD): -8.35 mmHg, 95% confidence interval (CI): -11.44, -5.25 mmHg versus control; MD: -9.88 mmHg, 95%CI: -12.62, -7.14 mmHg versus placebo] and diastolic BP (DBP) [MD: -7.62 mmHg, 95%CI: -11.20, -4.04 mmHg, versus control; MD: -8.79 mmHg, 95%CI: -11.92, -5.67 mmHg versus placebo]. Moreover, BP response rate and BP control rate after low-dose bisoprolol/hydrochlorothiazide combination treatment were significantly greater compared to control [odd ratio (OR) for response rate: 4.86, 95%CI: 2.52, 9.37; OR for control rate: 1.67, 95%CI: 1.11, 2.51]. Finally, treatment with low-dose bisoprolol/hydrochlorothiazide was associated with a reduced risk of any adverse event (AE) and peripheral edema compared to control. Conclusions: Overall, our results reaffirm the safety and efficiency of prescribing bisoprolol/hydrochlorothiazide combination treatment in stage I and II hypertension.

Even while accelerated cardiomyocyte apoptosis is one of the primary causes of cardiac damage, the underlying mechanism is still mostly unknown. In addition to examining potential protective effects of bisoprolol and diosmin against CoCl2-induced cardiac injury, the goal of this study was to identify potential mechanisms regulating the hypoxic cardiac damage caused by cobalt chloride (CoCl2). For a period of 21 days except Cocl2 14 days from the first day of the experiment, rats were split into the following groups: Normal control group, rats received vehicle only (2 ml/kg/day, p.o.), (Cocl2, 150 mg/kg/day, p.o.), bisoprolol (25 mg/kg/day, p.o.); diosmin (100 mg/kg/day, p.o.) and bisoprolol + diosmin + Cocl2 groups. At the end of the experimental period, serum was taken for estimation of cardiac function, lipid profile, and pro/anti-inflammatory cytokines. Moreover, tissue samples were collected for evaluation of oxidative stress, endothelial dysfunction, α-SMA, PKC-α, MiR-143-3P, MAPK, ERK5, MCP-1, CXCR4, Orai-1, and STIM-1. Diosmin and bisoprolol, either alone or in combination, enhance heart function by reducing abnormalities in the electrocardiogram and the hypotension brought on by CoCl2. Additionally, they significantly ameliorate endothelial dysfunction by downregulating the cardiac expressions of α-SMA, PKC-α, MiR-143-3P, MAPK, ERK5, MCP-1, CXCR4, Orai-1, and STIM-1. Bisoprolol and diosmin produced modulatory activity against inflammatory state, redox balance, and atherogenic index concurrently. Together, diosmin and bisoprolol, either alone or in combination, significantly reduced all the cardiac alterations brought on by CoCl2. The capacity to obstruct hypoxia-induced α-SMA, PKC-α, MiR-143-3P/MAPK/MCP-1, MiR-143-3P/ERK5/CXCR4, Orai-1/STIM-1 signaling activation, as well as their anti-inflammatory, antioxidant, and anti-apoptotic properties, may be responsible for these cardio-protective results.

UNASSIGNED: Several guidelines do not recommend beta-blocker as the first-line treatment for hypertension because of its inferior efficacy in stroke prevention. Combination therapy with beta-blocker is commonly used for blood pressure control. We compared the clinical outcomes in patients treated with amlodipine plus bisoprolol (A + B), a ß1-selective beta-blocker and amlodipine plus valsartan (A + V).
UNASSIGNED: A population-based cohort study was performed using data from the Taiwan National Health Insurance Research Database. From 2012 to 2019, newly diagnosed adult hypertensive patients who received initial amlodipine monotherapy and then switched to A + V or A + B were included. The efficacy outcomes included all-cause death, atherosclerotic cardiovascular disease (ASCVD) event (cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization), hemorrhagic stroke, and heart failure. Multivariable Cox proportional hazards model was used to evaluate the relationship between outcomes and different treatments.
UNASSIGNED: Overall, 4311 patients in A + B group and 10980 patients in A + V group were included. After a mean follow-up of 4.34 ± 1.79 years, the efficacy outcomes were similar between the A + V and A + B groups regarding all-cause death (adjusted hazard ratio [aHR] 0.99, 95% confidence interval [CI] 0.83-1.18), ASCVD event (aHR 0.97, 95% CI 0.84-1.12), and heart failure (aHR 1.06, 95% CI 0.87-1.30). The risk of hemorrhagic stroke was lower in A + B group (aHR 0.70, 95% CI 0.52-0.94). The result was similar when taking death into consideration in competing risk analysis. The safety outcomes were similar between the 2 groups.
UNASSIGNED: There was no difference of all-cause death, ASCVD event, and heart failure in A + B vs. A + V users. But A + B users had a lower risk of hemorrhagic stroke.

Chronic kidney disease (CKD) is a major contributor to morbidity and mortality in India. CKD often coexists with heart failure (HF), diabetes, and hypertension. All these comorbidities are risk factors for renal impairment. HF and CKD are pathophysiologically intertwined, and the deterioration of one can worsen the prognosis of the other. There is a need for safe renal pharmacological therapies that target both CKD and HF and are also useful in hypertension and diabetes. Neurohormonal activation achieved through the activation of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS), and the natriuretic peptide system (NPS) is fundamental in the pathogenesis and progression of CKD and HF. Angiotensin receptor neprilysin inhibitor (ARNi), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and selective β1-blocker (B1B) bisoprolol suppress this neurohormonal activation. They also have many other cardiorenal benefits across a wide range of CKD patients with or without concomitant HF, diabetes, or hypertension. This consensus statement from India explores the place of ARNi, SGLT-2i, and bisoprolol in the management of CKD patients with or without HF and other comorbidities.

OBJECTIVE: The present study compared the safety, efficacy, and tolerability of the new fixed-dose combination (FDC) of telmisartan 40 mg + bisoprolol 5 mg (TBP) tablets with the existing comparator FDC telmisartan 40 mg + metoprolol succinate ER 50 mg (TMS) tablets in patients with stage 1 and stage 2 hypertension.
METHODS: The multicentric, double-blind, parallel-group, comparative, prospective, phase-III clinical study involved 264 subjects with stage 1 and stage 2 hypertension from 10 centres across India. The selected subjects were randomized into two groups: group A received the TMS and group B received the new FDC TBP. The primary endpoint was the mean change in seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) from baseline to week 12 in both the control and study arms. The secondary endpoint was achieving the target of SeSBP <140 mmHg and SeDBP <90 mmHg from baseline to week 12 in both groups. Safety and tolerability parameters were evaluated in both groups based on adverse effects (AEs) reported by the patients and the physician.
RESULTS: Both treatment groups exhibited a reduction in BP after 2 weeks of treatment, which was sustained until 12 weeks. The mean change in SeSBP and SeDBP at weeks 2, 6, and 12 compared to the previous visit showed statistical significance (p < 0.001) in all cases for both groups A and B. The mean changes in SeSBP and SeDBP from baseline to study end were numerically higher in group B than in group A. The mean difference in SeSBP from baseline to study end was significantly higher in group B compared to group A (p = 0.029). By week 12, 88.28 % and 89.84 % of subjects in group B achieved SeSBP <140 mmHg and SeDBP <90 mmHg respectively, while 86.71 % and 91.40 % of subjects in group A achieved the same targets. Reported AEs were mostly mild to moderate in both treatment groups, and no serious AEs or deaths were reported. Tolerability was rated as \'excellent\' by 93.75 % of subjects in group B and 91.40 % of subjects in group A.
CONCLUSIONS: Both the new FDC TBP and the existing comparator TMS combination therapy have comparable efficacy, tolerability, and safety for the management of stage 1 and stage 2 hypertension.
UNASSIGNED: Clinical Trials Registry of India (CTRI) TRIAL REGISTRATION NO: CTRI/2021/11/037,926 PROTOCOL NO: MLBTL/05/2021 PROTOCOL URL: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=62069&EncHid=&userName=bisoprolol.

暂无摘要。

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that β-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission.
To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations.
The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023.
Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol.
The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions.
Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P = .72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P = .96).
Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both.
isrctn.org Identifier: ISRCTN10497306.

In India, heart failure (HF) is an important health concern affecting younger age groups than the western population. A limited number of Indian patients receive guideline-directed medical therapy (GDMT). Selective β-1 blockers (BB) are one of the GDMTs in HF and play an important role by decreasing the sympathetic overdrive. The BB reduces heart rate (HR) reverse the adverse cardiac (both ventricular and atrial), vascular, and renovascular remodeling seen in HF. Bisoprolol, a β-1 blocker, has several advantages and can be used across a wide spectrum of HF presentations and in patients with HF and comorbid conditions such as coronary artery disease (CAD), atrial fibrillation (AF), post-myocardial infarction (MI), uncontrolled diabetes, uncontrolled hypertension, and renal impairment. Despite its advantages, bisoprolol is not optimally utilized for managing HF in India. This consensus builds on updated evidence on the efficacy and safety of bisoprolol in HF and recommends its place in therapy with a focus on Indian patients with HF.

Despite the fact that the pathogenesis of cutaneous melanoma is shrouded in mystery, factors that have been neglected or unnoticed until now have come to the attention in recent years, and in all likelihood, they could also be pivotal. These factors, known as nitrosamines or NDSRIs, are characterized by high carcinogenic and mutagenic potency, and some of them have demonstrated these properties to human DNA as well. Unfortunately, these ingredients also turn up as contaminants in about 300 of the most widely distributed drugs worldwide. According to the most recent literature, some of these ingredients are also identified as potent photocarcinogens, as well as human carcinogens. The intake of these carcinogens in the context of polycontamination of polymedication, has been associated for years with the occurrence of melanomas. The need for cataloguing of nitrosamines , as well as their accurate labelling on drug packaging, would help to classify them even more accurately as carcinogens affecting human DNA. We present once again a patient , who developed nodular melanoma within the context of the intake of 3 potentially nitrosamine/ NDSRIs contaminated antihypertensive drugs (valsartan/ Hydrochlorothiazide/ bisoprolol). Pathogenetic aspects concerning drug-induced nitrosogenesis, photocarcinogenesis and oncopharmacogenesis of skin cancer are discussed. Nitrosogenesis\' of Cancer as concept in the medical literature has been known for decades, but in relation to other forms of human cancer. Exogenously mediated drug-mediated nitrosogenesis is a logically conditioned and newly defined concept whose significance with respect to the clinical manifestation of skin cancer is only beginning to grow.