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1.
Journal of Clinical and Diagnostic Research ; 16(9):XD01-XD03, 2022.
Article in English | EMBASE | ID: covidwho-2033408

ABSTRACT

Chronic lymphocytic leukaemia is a haematological malignancy that occurs due to an increased proliferation of mature B lymphocytes. It is considered to be the most common leukaemia in adults. Hyponatremia is commonly seen in such patients. This case report is about a 75-year-old male, who presented with giddiness, followed by altered sensorium. However, the patient had no motor weakness or sensory loss. Initially, a diagnosis of posterior circulation stroke was made but Magnetic Resonance Imaging (MRI) brain did not show associated signs. The routine investigations showed highly elevated total leukocyte count and hyponatremia. The patient was worked up for malignancy and diagnosed with Chronic lymphocytic leukaemia. Oncology reference was taken and treated with tablet Ibrutinib. On discharge, the patient's mentation improved, and he is on regular follow-up.

2.
Journal of the ASEAN Federation of Endocrine Societies ; 37:50-51, 2022.
Article in English | EMBASE | ID: covidwho-2006562

ABSTRACT

Introduction Phaeochromocytoma and paraganglioma (PPGL) are rare tumors with up to 40% associated with inherited germline mutations. SHDB mutation is associated with an increased risk of metastasis. Case A 36-year-old male presented with hypertensive emergency. He was diagnosed to have a bladder paraganglioma at age 32 when he presented with hypertensive crisis. Ga-68 DOTANOC PET/CT scan then showed a localized 4.7 x 5.3 cm bladder paraganglioma and he underwent complete surgical resection with resolution of his symptoms. Genetic testing done showed SHDB, deletion (exon 1), heterogenous pathogenic variant. He remained asymptomatic and was lost to follow-up due to COVID-19 until his recent admission. During this admission, he had labile blood pressure with symptoms of palpitations and lethargy. He was found to have a 4.3x elevated urine normetanephrine (1639 ug/day, N<374.7). Metanephrine and 3-methoxytyramine levels were normal. His blood pressure was controlled with phenoxybenzamine 20 mg TDS (1 mg/kg), telmisartan 40 mg OM and carvedilol 25 mg BD with improvement in his symptoms. Subsequent anatomical imaging with CT and functional imaging with Ga-68 DOTATATE showed a small recurrence at the bladder wall with metastatic lesions at the left sacral ala measuring 4.5 x 5.1 cm, and multiple lytic lesions over the spine, ribs and also the left acetabulum with the highest uptake of Ga-68 DOTATATE at the C2 vertebra (SUV max 93). He is now planned for peptide receptor radionuclide therapy (PRRT). SHDB mutation is associated with a higher risk of metastatic disease which has remained unexplained. Treatment for metastatic disease include surgical resection where possible, targeted therapy such as PRRT, meta-iodobenzylguanidine (MIBG) therapy, radiotherapy and also systemic therapy such as chemotherapy and tyrosine kinase inhibitors. Conclusion Patients with PPGL, especially those with SHDB mutation, require monitoring at regular intervals to screen and detect metastasis to reduce mortality and morbidity.

3.
Journal of Cardiovascular Disease Research ; 13(1):884-893, 2022.
Article in English | EMBASE | ID: covidwho-1887445

ABSTRACT

The prevalence of Pheochromocytoma in pat ient with hypertension is 0.1 -0.6%. These types of tumours are known for unpredictable perioperative course and hemodynamic instability. Various different drugs and anaesthesia techniques can be used to tackle these situations. Dexmedetomidine is emerged as newer agent with better hemodynamic stability, reducing requirement of other anaesthesia drugs, blunting of sympathoadrenal response in resection of Pheochromocytoma. We report four cases operated between January 2021 to June 2021.Preoperative preparation was done with α and β blockade. Dexmedetomidine was used during induction as 1 mcg/kg over 10 mins followed by 0.7mcg/kg/hr intraoperatively. Combination of Dexmedetomidine, Fentanyl, NTG, Isoflurane and Epidural analgesia was used. IF needed boluses of Esmolol and Labetalol were used during tumor manipulation. All the patients had an uneventful perioperative course. Dexmedetomidine with pre-operative α and β blockade reduce the need of other drugs intraoperatively and can be used as anaesthetic adjunct to maintain steady hemodynamic.

4.
Comput Struct Biotechnol J ; 20: 2091-2111, 2022.
Article in English | MEDLINE | ID: covidwho-1778074

ABSTRACT

The discovery and facile synthesis of a new class of sartan-like arterial antihypertensive drugs (angiotensin receptor blockers [ARBs]), subsequently referred to as "bisartans" is reported. In vivo results and complementary molecular modelling presented in this communication indicate bisartans may be beneficial for the treatment of not only heart disease, diabetes, renal dysfunction, and related illnesses, but possibly COVID-19. Bisartans are novel bis-alkylated imidazole sartan derivatives bearing dual symmetric anionic biphenyl tetrazole moieties. In silico docking and molecular dynamics studies revealed bisartans exhibited higher binding affinities for the ACE2/spike protein complex (PDB 6LZG) compared to all other known sartans. They also underwent stable docking to the Zn2 + domain of the ACE2 catalytic site as well as the critical interfacial region between ACE2 and the SARS-CoV-2 receptor binding domain. Additionally, semi-stable docking of bisartans at the arginine-rich furin-cleavage site of the SARS-CoV-2 spike protein (residues 681-686) required for virus entry into host cells, suggest bisartans may inhibit furin action thereby retarding viral entry into host cells. Bisartan tetrazole groups surpass nitrile, the pharmacophoric "warhead" of PF-07321332, in its ability to disrupt the cysteine charge relay system of 3CLpro. However, despite the apparent targeting of multifunctional sites, bisartans do not inhibit SARS-CoV-2 infection in bioassays as effectively as PF-07321332 (Paxlovid).

5.
2021 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2021 ; : 2587-2594, 2021.
Article in English | Scopus | ID: covidwho-1722868

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a worldwide pandemic (COVID-19). Drug repurposing studies, including drugs such as dexamethasone (DEX), chloroquine (CQ), and telmisartan (TLS), have been performed in COVID-19 clinical trials. DEX and CQ have been demonstrated in vitro to bind angiotensin-converting enzyme 2 (ACE2), a cellular entry receptor utilized by SARS-CoV-2. However, how DEX/CQ bind to ACE2 and their mechanisms of action are still unknown. We demonstrated that DEX, CQ, and TLS disrupt the interactions between SARS-CoV-2 spike protein and human ACE2 via binding to an allosteric site close to the viral spike protein binding region at the peptidase domain of ACE2, causing a conformational change of the ACE2. We defined four conformational states of ACE2 based on the two helices distances. Our molecular dynamics simulations suggested that binding to the viral spike protein shifted ACE2 conformation populations away from 'Open' conformation. Such conformation population shift is further enhanced by the Delta variant. The binding of the drugs to ACE2 rescues this conformation population shift allosterically to keep ACE2 in 'Open' conformation mostly. Our findings provide a potential insight that modulating the conformation of ACE2 may prevent SARS-CoV-2 invasion due to unfavored poses for spike protein binding. © 2021 IEEE.

6.
Life Sci ; 293: 120284, 2022 Mar 15.
Article in English | MEDLINE | ID: covidwho-1620913

ABSTRACT

AIMS: Angiotensin-converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin system (RAS) recently identified as the membrane receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we aim to study whether two receptors from RAS, the angiotensin receptor type 1 (AT1R) and the bradykinin 2 receptor (B2R) modulate ACE2 internalization induced by a recombinant receptor binding domain (RBD) of SARS-CoV-2 spike protein. Also, we investigated the impact of ACE2 coexpression on AT1R and B2R functionality. MATERIALS AND METHODS: To study ACE2 internalization, we assessed the distribution of green fluorescent protein (GFP) signal in HEK293T cells coexpressing GFP-tagged ACE2 and AT1R, or B2R, or AT1R plus B2R in presence of RBD alone or in combination with AT1R or B2R ligands. To estimate ACE2 internalization, we classified GFP signal distribution as plasma membrane uniform GFP (PMU-GFP), plasma membrane clustered GFP (PMC-GFP) or internalized GFP and calculated its relative frequency. Additionally, we investigated the effect of ACE2 coexpression on AT1R and B2R inhibitory action on voltage-gated calcium channels (CaV2.2) currents by patch-clamp technique. KEY FINDINGS: RBD induced ACE2-GFP internalization in a time-dependent manner. RBD-induced ACE2-GFP internalization was increased by angiotensin II and reduced by telmisartan in cells coexpressing AT1R. RBD-induced ACE2-GFP internalization was strongly inhibited by B2R co-expression. This effect was mildly modified by bradykinin and rescued by angiotensin II in presence of AT1R. ACE2 coexpression impacted on B2R- and AT1R-mediated inhibition of CaV2.2 currents. SIGNIFICANCE: Our work contributes to understand the role of RAS modulators in the susceptibility to SARS-CoV-2 infection and severity of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , Receptor, Angiotensin, Type 1/biosynthesis , Receptor, Bradykinin B2/biosynthesis , Spike Glycoprotein, Coronavirus/administration & dosage , Angiotensin II/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme 2/analysis , Green Fluorescent Proteins/analysis , Green Fluorescent Proteins/biosynthesis , HEK293 Cells , Humans , Receptor, Angiotensin, Type 1/analysis , Receptor, Bradykinin B2/analysis , Recombinant Proteins/administration & dosage
7.
European Heart Journal ; 42(SUPPL 1):2965, 2021.
Article in English | EMBASE | ID: covidwho-1554057

ABSTRACT

Background: The imbalance of the Renin Angiotensin System in favor of the angiotensin II has been described in Covid-19-patients. Angiotensin II regulates life processes, such as cell growth and division and can promote apoptosis initiating an inflammatory process with release of proinflammatory cytokines. Angiotensin receptor blockers (ARBs) block the AT1 receptor and could have a beneficial effect reducing Covid-19 inflammation. Purpose: To assess whether Telmisartan is effective in reducing C-reactive protein (CRP) plasma levels in hospitalized patients with Covid-19, and improves clinical outcomes and length of stay and morbimortality. Trial design: This is a parallel-group, randomized, two-arm, open-label, multicenter superiority trial with 1:1 allocation ratio. Methods: Inclusion criteria: patients aged more than 18 years with less than 5 days of symptoms onset and after informed consent was obtained. Exclusion criteria: Patients admitted to intensive care unit (ICU) or using mechanical ventilatory support or ongoing ARBs / angiotensin-converting enzyme inhibitors treatment at the time of randomization. Control arm received standard care alone and treatment arm Telmisartan 80 mg bid 14 days added to standard care. Primary outcome were CRP plasma levels at day 5 and 8 after randomization. Secondary outcomes included time to discharge at 15 days, admission to ICU and death at 15 and 30 days. Results: 158 patients were included in the analysis, 80 in the control and 78 in the telmisartan group. Day 5 control-group CRP levels were 6.06±6.95 mg/dL (n=66) while telmisartan group were 3.83±5.08 mg/dL (mean±SD;n=66, p<0.05). Day 8 CRP levels were 6.30±8.19 mg/dL (n=44) and 2.37±3.47 mg/dl (mean±SD;n=43, p<0.05) in the control and telmisartan groups, respectively. Kaplan-Meier analysis showed that Telmisartan-treated patients had lower median time to discharge (control= 15 days;telmisartan=9 days). Death by day 30 was reduced by 81% in the telmisartan-treated group (control 22.54%, 16/71;telmisartan 4.29%, 3/70 participants;p=0.0023). Composite ICU, mechanical ventilation or death was reduced by telmisartan treatment at days 15 and 30. No telmisartan-related adverse events were reported. Conclusions: Telmisartan, an inexpensive safe drug, in high doses, demonstrated anti-inflammatory effects and reduced morbimortality in Covid-19-hospitalized patients.

8.
J Clin Hypertens (Greenwich) ; 23(9): 1664-1674, 2021 09.
Article in English | MEDLINE | ID: covidwho-1354498

ABSTRACT

This multicenter, phase 4, Prospective Randomized Open, Blinded End-point (PROBE) study aimed to evaluate safety and efficacy of telmisartan/rosuvastatin single-pill combination (SPC) therapy on lowering central blood pressure (BP) compared with telmisartan monotherapy in hypertensive patients with dyslipidemia in Korea. Study was terminated earlier than planned due to COVID-19 pandemic, thus should be considered as a pilot study. Among 125 patients who met the inclusion criteria of hypertension and dyslipidemia (defined as 10-year Atherosclerotic Cardiovascular Disease risk score over 5%), 80 patients went through 4-week single-group run-in period with telmisartan 40-80 mg, then randomized to telmisartan 80 mg + rosuvastatin (10 or 20 mg) SPC group or telmisartan 80 mg monotherapy group. The central/brachial BP, brachial-ankle pulse wave velocity (baPWV), and augmentation index (AIx) were assessed at baseline and 16 weeks later. Mean brachial SBP changed from 135.80 ± 14.22 mmHg to 130.69 ± 13.23 mmHg in telmisartan/rosuvastatin group and from 134.37 ± 12.50 mmHg to 133.75 ± 12.30 mmHg in telmisartan monotherapy group without significant difference (between-group difference p = .149). Mean central SBP were reduced significantly in the telmisartan/rosuvastatin group with change from 126.72 ± 14.44 mmHg to 121.56 ± 14.56 mmHg while telmisartan monotherapy group showed no significant change (between-group difference p = .028). BaPWV changed from 1672.57 ± 371.72 m/s to 1591.75 ± 272.16 m/s in telmisartan/rosuvastatin group and from 1542.85 ± 263.70 m/s to 1586.12 ± 297.45 m/s in telmisartan group with no significance (between-group difference p = .078). Change of AIx had no significant difference (between-group difference p = .314). Both groups showed excellent compliance rate of 96.9 ± 4.5% with no significant difference in adverse rate. Telmisartan/rosuvastatin SPC therapy was more effective in lowering central BP compared with the telmisartan monotherapy. The results of this study showed benefit of additive statin therapy in hypertensive patients combined with dyslipidemia.


Subject(s)
COVID-19 , Dyslipidemias , Hypertension , Ankle Brachial Index , Antihypertensive Agents/therapeutic use , Benzoates , Blood Pressure , Drug Combinations , Dyslipidemias/drug therapy , Humans , Hypertension/drug therapy , Pandemics , Pilot Projects , Prospective Studies , Pulse Wave Analysis , Rosuvastatin Calcium , SARS-CoV-2 , Telmisartan/pharmacology
9.
EClinicalMedicine ; 37: 100962, 2021 07.
Article in English | MEDLINE | ID: covidwho-1275283

ABSTRACT

Background: Angiotensin receptor blockers (ARBs), such as telmisartan, have been postulated to treat Covid-19-induced lung inflammation. Methods: This is a parallel-group, randomized, two-arm, open-label, adaptive, multicenter superiority trial with 1:1 allocation ratio. Participants included patients from 18 years of age hospitalized with Covid-19 with 4 or fewer days since symptom onset enrolled at a university and a community hospital in Buenos Aires, Argentina. Exclusion criteria included prior intensive care unit (ICU) admission and use of ARBs/angiotensin converting enzyme inhibitors at randomization. Control arm received standard care alone and treatment arm telmisartan 80 mg twice daily for 14 days. Primary outcomes were C-reactive protein (CRP) plasma levels at day 5 and 8 after randomization. Secondary outcomes included time to discharge within 15 days, admission to ICU and death at 15- and 30-days. NCT04355936 (Completed). Findings: A pragmatic decision to end the study before the third interim analysis was made on Oct. 30th due to sharp reduction in recruitment. A total of 162 patients were randomized. 158 patients enrolled between May 14 and October 30 2020, were included in the analysis, 80 in the standard care and 78 in the telmisartan added to standard care group. Baseline absolute CRP serum levels were 5.53 ± 6.19 mg/dL (95% CI 6.91 to 4.15, n = 80) and 9.04 ± 7.69 (95% CI 9.04 to 10.82, n = 74) in the standard care and telmisartan added to standard care groups, respectively. Day 5 control-group CRP levels were 6.06 ± 6.95 mg/dL (95% CI 7.79-4.35, n = 66) while telmisartan group were 3.83 ± 5.08 mg/dL (95% CI 5.08-2.59, n = 66, p = 0.038). Day 8 CRP levels were 6.30 ± 8.19 mg/dL (95% CI 8.79-3.81, n = 44) and 2.37 ± 3.47 mg/dL (95% CI 3.44-1.30, n = 43, p = 0.0098) in the control and telmisartan groups, respectively (all values expressed as mean ± SD). Kaplan-Meier analysis showed that telmisartan-treated patients had a lower median time-to-discharge (control=15 days; telmisartan=9 days). Death by day 30 was reduced in the telmisartan-treated group (control 22.54%, 16/71; telmisartan 4.29%, 3/70 participants; p = 0.0023). Composite ICU, mechanical ventilation or death was reduced by telmisartan treatment at days 15 and 30. No adverse events were reported. Interpretation: Our study suggests that the ARB telmisartan, a widely used antihypertensive drug, is safe and could reduce morbidity and mortality in hospitalized patients infected with SARS -CoV-2 by anti-inflammatory effects. Further studies employing telmisartan are needed for confirmation of our results and to define its true therapeutic value as a tool against Covid-19.

10.
Front Pharmacol ; 12: 603736, 2021.
Article in English | MEDLINE | ID: covidwho-1186854

ABSTRACT

COVID-19 pandemic demands a swift response to find therapeutic tools that effectively reduce morbidity and mortality. Despite initial fears, evidence from retrospective observational studies supports the inhibition of the renin-angiotensin system as an emerging pathway to delay or moderate angiotensin II-driven lung inflammation. This has triggered several prospective clinical trials. In this commentary we provide an overview and analysis of current ongoing clinical trials aimed at evaluating the therapeutic efficacy of angiotensin receptor blocker (ARB) use in COVID-19. The relevance of the results of these trials will have to be interpreted depending on the stage and severity of the disease and in light of the start time of their prescription related to the time of diagnosis of COVID-19 as well as the administered doses.

11.
Drug Dev Res ; 81(7): 768-770, 2020 11.
Article in English | MEDLINE | ID: covidwho-155438

ABSTRACT

In late 2019, a new coronavirus emerged in Wuhan Province, China, causing lung complications similar to those produced by the SARS coronavirus in the 2002-2003 epidemic. This new disease was named COVID-19 and the causative virus SARS-CoV-2. The SARS-CoV-2 virus enters the airway and binds, by means of the S protein on its surface to the membrane protein ACE2 in type 2 alveolar cells. The S protein-ACE2 complex is internalized by endocytosis leading to a partial decrease or total loss of the enzymatic function ACE2 in the alveolar cells and in turn increasing the tissue concentration of pro-inflammatory angiotensin II by decreasing its degradation and reducing the concentration of its physiological antagonist angiotensin 1-7. High levels of angiotensin II on the lung interstitium can promote apoptosis initiating an inflammatory process with release of proinflammatory cytokines, establishing a self-powered cascade, leading eventually to ARDS. Recently, Gurwitz proposed the tentative use of agents such as losartan and telmisartan as alternative options for treating COVID-19 patients prior to development of ARDS. In this commentary article, the authors make the case for the election of telmisartan as such alternative on the basis of its pharmacokinetic and pharmacodynamic properties and present an open-label randomized phase II clinical trial for the evaluation of telmisartan in COVID-19 patients (NCT04355936).


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , COVID-19/drug therapy , SARS-CoV-2/physiology , Telmisartan/therapeutic use , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Clinical Trials, Phase II as Topic , Humans , Lung/metabolism , Lung/virology , Pandemics , Protein Binding/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Telmisartan/pharmacology , Virus Internalization/drug effects
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