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COVID- 19 was the most challenging public health problem worldwide for better part of 2 years (2019 - 2021). Although several of the medication have not demonstrated promising benefits in the majority of research, they are nonetheless utilized. The purpose of this study was to compare and contrast the hospital pharmaceutical care of COVID-19 patients by sex, age group, and with regards to oxygen consumption classifying and grouping them with comorbidities seen and auxiliary medication given . Hospital based retrospective observational study was conducted among 123 patients with antigen positive Reverse Transcriptase Polymerase Chain Reaction confirmed COVID- 19 infection admitted in the ICU for 24 hours prior. As the age increased the chance for ICU admission also increased. The most affected age group was above 50 years of age. The total number of patients requiring oxygen was 100% in COVID- 19 ICU patients. Some of the most common comorbidities were heart disease (18%) followed by Diabetes Mellitus (15%) and Hypertension (15 %). Only 48 % of patients received antivirals. Remdesivir which was the mainstay antiviral was given (41%). Amoxicillin and clavulanate combination (Augmentin 625 mg) was the most commonly prescribed antibiotic (27%).The antipyretic of choice was paracetamol which was given to 100% of patients. Almost all patients (78%) were given enoxaparin sodium as the anticoagulant of choice. Regardless of equivocal results, multivitamins and supplements were recommended to all patients. All prescription guidelines as given by ICMR for COVID- 19 ICU patients were followed with the exception of the extensive antimicrobial use.Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.
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SESSION TITLE: A Look Into Poisoning and Drug Overdoses SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 12:25 pm - 01:25 pm INTRODUCTION: We present a case of a 64-year-old woman with severe obesity (BMI 53) who presented with shock after beta-blocker (BB) and calcium channel-blocker (CCB) overdose. CASE PRESENTATION: The patient presented after an intentional suicide attempt, taking multiple antihypertensive medications, including tablets of nifedipine 90mg, carvedilol 25mg, and losartan 100mg. She had also been experiencing shortness of breath and lower extremity pain for several days. Upon arrival, she was lethargic and minimally responsive, and was found to be in shock with a heart rate 63. She was intubated for airway protection and started on multiple vasopressors including norepinephrine, phenylephrine, vasopressin, dopamine and epinephrine for circulatory support. She was also found to be positive for SARS-CoV-2. She was given activated charcoal, received gastric lavage, and whole bowel irrigation. She received a bolus of regular insulin at 1U/kg, and subsequently started on a high-dose insulin infusion titrated to 11U/kg/h along with dextrose infusion and calcium gluconate. By day four of admission, vasopressor requirements had been reduced to only norepinephrine and the insulin infusion had been successfully discontinued. However, her hospital course was further complicated MRSA and Pseudomonas pneumonia, and renal failure requiring hemodialysis. She continued to develop refractory shock, and remained over 50 liters net positive. Her condition progressively deteriorated and her gross volume overload was difficult to manage, and ultimately expired on day ten of admission. DISCUSSION: The management of CCB and BB overdose has been studied, with hyperinsulinemic euglycemic therapy (HIET)1,2 as our choice. Our patient's decline was likely secondary to the high volumes of dextrose infusion required after HIET. With underlying renal failure, insulin clearance proved to be a significant challenge. Such severe obesity with a weight-based regimen resulted in over 1500U insulin/hr at any given point with our patient. Renal clearance is governed by a proportion of t/V, where t denotes length of a dialysis session and V the volume of fluid in the patient's body.3 Patients with significant volume would require extensive dialysis sessions and fluid balances would be challenging. Continuous renal replacement therapy (CRRT) was attempted later in her hospital course. However, the patient was not able to tolerate it as she had progressed to multiorgan failure. CONCLUSIONS: HIET has shown to be a successful management strategy for CCB and BB overdose. However, weight-based dosing can prove to be a challenge in patients with severe obesity. CRRT should be considered early in severely obese patients that undergo HIET, given the rapid accumulation of fluid secondary to the large-volume insulin and dextrose infusions. Further investigations should look into identifying maximal safe dosages of HIET, especially in severely obese patients. Reference #1: Cole JB, Arens AM, Laes JR, Klein LR, Bangh SA, Olives TD. High dose insulin for beta-blocker and calcium channel-blocker poisoning. Am J Emerg Med. 2018 Oct;36(10):1817-1824. doi: 10.1016/j.ajem.2018.02.004 Reference #2: Krenz JR, Kaakeh Y. An Overview of Hyperinsulinemic-Euglycemic Therapy in Calcium Channel Blocker and β-blocker Overdose. Pharmacotherapy. 2018 Nov;38(11):1130-1142. doi: 10.1002/phar.2177 Reference #3: Turgut F, Abdel-Rahman E, M: Challenges Associated with Managing End-Stage Renal Disease in Extremely Morbid Obese Patients: Case Series and Literature Review. Nephron 2017;137:172-177. doi: 10.1159/000479118 DISCLOSURES: No relevant relationships by Alejandro Garcia No relevant relationships by Vishad Sheth no disclosure on file for Andre Sotelo;
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CASE: This is a 41-year-old man who was admitted to the medical floor with mild COVID-19 symptoms without hypoxia. He had End Stage Renal Disease (ESRD) on Hemodialysis (HD), failed renal transplant, Hypertension and Schizophrenia. Patient had no relevant family history. Medications included Aspirin, Atorvastatin, Nifedipine, Benztropine, and Haloperidol. Patient had allergy to shellfish products. He tested positive a week prior to admission with mild cough no fever or hypoxia. As symptoms worsened, he presented to emergency department and was admitted because of his immunocompromised status. The night of admission, he developed wheezing and stridor, swelling of face and lips, and altered mental status. It was difficult to pass endotracheal tube due to swollen airways. Vital signs were stable except for a low oxygen saturation. Physical examination significant for stridor and swelling of the face and lips. Laboratory values were not significant. We reviewed and none of them was newly started or associated with risks of angioedema. He had no history of previous similar episodes. Patient was given anti-histamines and steroids with slight improvement. Flexible laryngoscopy was performed showing swollen epiglottis and aryepiglottic folds. He ended up getting a tracheostomy as he was regarded as a high risk to be liberated from intubation. IMPACT/DISCUSSION: Few other cases of COVID-associated angioedema have been reported in the literature, majority of the cases explained were in African American patients. The features of angioedema reported like the traditional angioedema, swelling of the face, lips and airways. This angioedema developed within 7 days of detection of COVID-19 in our case and >10 days in the previously reported cases. Angioedema develops due to increased levels of Bradykinin (BK) and its metabolites due to increased expression or decreased degradation. Angiotensin Converting Enzyme (ACE) with other enzymes prevent angioedema by degradation of BK and its metabolites . African Americans, have genetic susceptibility which leads to lower levels of other enzymes involved in the Bradykinin metabolism, thus ACE blockade put them at a higher risk of angioedema. The association of COVID-19 with ACE2 and its subsequent disruption of ACE activity is thought to be the reason behind the development of angioedema. Most of the published articles are either observational or sporadic case reports. More thorough study might help identify further mechanisms and if there is a direct true causal relationship between COVID-19 infection and angioedema or if it is the result of a “second hit,” as it was called by authors of another case that involved a Caucasian male with hypertension who has been using Lisinopril for years with no previously reported complaint. CONCLUSION: SARS CoV-2 should be suspected as cause for angioedema. Further studies needed to establish modalities for diagnosis, management and prevention in high-risk patients.
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Background: Dysgeusia is a distortion of taste sensation. Etiologies can include medications and Covid-19, among others. Dysgeusia may lead to appetite loss which is nonspecific and can have multiple causes, including major depressive disorder (MDD) (Coulter, 1988). Although post-marketing data revealed no association between nifedipine and dysgeusia (Ackerman, 1997), case reports of dysgeusia from nifedipine exist (Ackerman, 1997). We present a case of nifedipine-induced dysgeusia mistaken for depression. Case Report: A 42-year-old man with hypertension and diabetes was admitted to the hospital following right thalamocapsular and intraventricular hemorrhages. Hypertension was managed with metoprolol, lisinopril, nifedipine, and chlorthalidone. Levetiracetam was started for seizure prophylaxis. Medications included pantoprazole, simethicone, transdermal lidocaine, insulin, metformin, docusate, senna, and subcutaneous heparin. Psychiatric consultation was requested out of concern that appetite loss indicated depression. The day before psychiatric evaluation, mirtazapine 15 mg at bedtime for mood and appetite was started. Nifedipine 90 mg daily had been started 9 days prior to his first complaint of decreased appetite. The patient reported feeling disconnected from his family and “sad" for ∼10 years, complaining that family members “talk behind his back.” He was otherwise without paranoia. He denied insomnia, anhedonia, hopelessness, poor concentration, suicidal ideation, homicidal ideation, guilt, mania, or hallucinations. He reported poor appetite due to epigastric discomfort and bad taste to foods. Covid-19 testing was not yet widely available. No other signs or symptoms suggestive of Covid-19 were present. Although alert and fully oriented, concentration was impaired with sometimes tangential thought processes. Affect was full without depression. A diagnosis of adjustment disorder was made. The psychiatry team suspected nifedipine-induced dysgeusia and advised discontinuing nifedipine. Appetite improved two days later. Discussion: This case highlights the importance of considering alternative causes of nonspecific symptoms of depression, including decreased appetite, that may have non-psychiatric causes. Dysgeusia is widely recognized as a symptom of Covid-19. Other causes, including medications may be underrecognized and amenable to intervention. Conclusion: It would be helpful to consider medication side-effects as potential causes for taste distortion alongside psychiatric diagnoses, and COVID-19. References: 1. Coulter DM: Eye pain with nifedipine and disturbance of taste with captopril: a mutually controlled study showing a method of post marketing surveillance BMJ 1988;296: 1086–8. 2. Ackerman BH, Kasbekar N: Disturbances of taste and smell induced by drugs. Pharmacotherapy 1997;17(3):482-96.
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Background: Nifedipine is a calcium channel-blocking drug, common antihypertensive medication. Gingival tissue enlargement is a frequent periodontal side effect, associated to the presence of dental plaque. Description of the procedure: In January 2018, a male 62-year-old patient was evaluated at the Dentistry Department of Coimbra University Hospital. His main complaint was gingival “swelling” and masticatory difficulty. Anamnesis revealed hypertension medicated with Nifedipine for 8 years. Besides partial edentulism and tooth migration, oral observation highlighted severe bimaxillary gingival enlargement, not restricted to the papillae, pronounced inflammation and periodontal attachment loss. Periodontal screening revealed 10 mm probing depth (PD) at several interdental sites, maximum clinical attachment loss (CAL) of 5 mm, bleeding on probing (BOP) of 61% and plaque index (PI) of 100%. The patient was diagnosed Nifedipine Gingival Enlargement with a Generalized Stage IV, Grade B Periodontitis. Non-surgical periodontal treatment was initiated with oral hygiene instructions, supra and subgingival instrumentation. Simultaneously, his assistant physician replaced nifedipine with enalapril. The patient attended regular periodontal appointments for 12 months. A decrease in gingival enlargement was noted in the subsequent months. Due to COVID-19 restrictions, patient was only reevaluated in May 2021. Outcomes: Three years after replacement of nifedipine and nonsurgical periodontal treatment, gingival enlargement was resolved. Periodontitis was stabilized, as periodontogram revealed a mean reduction PD of 6 mm at the deepest sites, grade II furcation involvements, BOP of 10% and PI of 34%. Step 3 periodontal therapy could be initiated. Due to economic restrictions, oral rehabilitation could not be fulfilled. Conclusions: Severe gingival tissue enlargement related to nifedipine in a periodontitis IVB patient was resolved by non-surgical periodontal treatment. Meticulous plaque control is mandatory. Communication with the Physician is important to alter the medication and restore patient's quality of life.
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A 51-year-old woman presented acutely to dermatology with an 8-week history of painful, purple discolouration of her toes, which started on her left foot but progressed to involve all of her toes. She was noted to have a positive COVID-19 polymerase chain reaction test after her symptoms began. There was some superficial ulceration of two of her toes. The episode lasted for 5 weeks;however, after 6 weeks her toes had flared again. No triggers were indentified;in particular, her symptoms were not related to the cold. There were no other rashes. She has a past medical history of endometriosis and gout. She takes desogestrel and allopurinol, which she had been on for 2 years. Vasculitis screen was negative. She was treated initially with clobetasol propionate and nifedipine. On follow-up 6 weeks later, the patient reported hypersensitivity of her toes, with severe pain reported from socks rubbing against her toes. The toes had normal appearances and cool peripheries. We suspect that the increased sensitivity and pain is a reflex sympathetic response secondary to 'COVID toes' and have treated with it gabapentin. It is thought that reflex sympathetic dystrophy occurs because inflammation causes damage to the nerves;however, the exact mechanism behind reflex sympathetic dystrophy is yet to be elucidated.
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Aim To define COVID toes and fingers in paediatrics, and to explain the aetiology, the assessment and investigation management, the diagnosis, the clinical presentation and the care management including the use of oral nifedipine in this newly found disease during the COVID-19 pandemic. In addition, we will illustrate the process using the multi-disciplinary approach to prepare the Paediatric COVID toes guideline in our Trust, and to cite some examples of the related patient cases seen in our hospital as well as to summarise the total number of patient cases seen to date. Method To carry out a literature search to find out the latest related articles and clinical studies, and to summarise the findings to prepare for the drafting of the clinical guideline. This guideline was initially prepared by the medical team and was then reviewed using multi-disciplinary team (MDT) approach including the paediatric pharmacists and the consultation from the tertiary paediatric centre. We also summarised the number of paediatric patient cases that were seen in our Trust and categorised them into different age groups, ethics background, and referral systems. Results A number of related articles were found after the literature search. The first draft of the Paediatric COVID-toes guideline was prepared in March 2021 and it was then reviewed by the MDT in the Paediatric Clinical Guideline Group of our Trust. The paediatric pharmacist expressed her comments including the drug of choice such as oral nifedipine, the dosages below and above 2 years of age, the evidence to support the dosage recommendations, the different formulations available in the market for oral nifedipine such as oral suspension, capsule, tablet and modified-released (MR) tablet, recommended effective method for oral administration, side effects profile, monitoring such as blood pressure, patient counselling and education, and provision of patient leaflet and video-link to aid patient compliance. Conclusion The final version of the Paediatric COVID toes guideline was prepared by the multi-disciplinary team in July, 2021, and it was uploaded in the Trust intranet in August 2021. In view of the literature search, there is limited evidence to support the use of oral nifedipine under 2 years of age for this indication. In our guideline, we recommend the dose of nifedipine to be 2.5-10 mg 2-4 times a day for children age 2 to 17 years old, starting with low doses at night and increase gradually by closely monitoring blood pressure and other side effects. The use of oral nifedipine is unlicensed for this indication in children. In our guideline, we recommend the use of oral MR nifedipine tablet after the consultation with the tertiary centre. Oral suspension is not routinely used. During counselling session, the pharmacist will advise the parent/carer to crush and dissolve the MR tablet in water and give appropriate dose accordingly. To date, 15 patients diagnosed with this disease were seen in our clinic. They are mainly referred to the clinic via the Accident and Emergency Department. The patient ages are all above 8 years old and they are mainly of Asian ethical background.
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Background/Aims Chilblain-like lesions (perniosis) have been reported frequently during COVID-19 pandemic in children and adolescents with no history of exposure to cold temperatures or underlying autoimmune conditions. Patients with these skin changes reported mild COVID-19 symptoms or previous contact with confirmed COVID-19 cases before they became symptomatic. In the majority of cases, a causal relationship between SARS-CoV-2 infection and chilblain-like lesion has not been proven. Methods Retrospective review of patients with chilblain-like lesions, possibly secondary to SARS-CoV-2 infection, presenting to a tertiary Adolescent Rheumatology service between January and August 2021. Results We identified five, male, adolescent patients (mean age, 16 years old) who presented with new onset of chilblain-like lesions affecting fingers, toes and heels in December 2020, which coincided with the peak of second wave of COVID-19 infection. One month prior to skin changes occurrence, 3 out of 5 patients experienced mild respiratory COVID-19-like symptoms and the rest of the patients were asymptomatic but were in contact with COVID-19 positive cases following outbreaks in schools. 1 of 3 symptomatic patients had a positive COVID-19 PCR test prior to skin manifestations. 2 out of 4 patients with heel lesions had deep, full thickness skin loss heel ulcers and 2 of 5 patients had superficially ulcerated lesions on a finger and toes, respectively, resulting in inability to attend school. None of the patients had any other symptoms or signs to suggest an underlying autoimmune connective tissue disorder. Demographics, clinical features and serological data are summarised in Table 1. One patient underwent a biopsy of heel ulcer which was histologically consistent with perniosis. In two patients (40%) chilblain like lesions resolved spontaneously within 2 months. Three patients (60%), with progressive ulcerated lesions, required various combinations of treatments with aspirin, calcium channel blockers (nifedipine), topical or oral steroids and hydroxychloroquine with complete resolution of symptoms within 6 months. Conclusion Chilblain-like lesions, including heel involvement associated with mildly symptomatic COVID-19 infection, have been reported before. Our mini-case series raises awareness of ulcerating chilblain like lesions possibly secondary to COVID-19 in adolescent patients, which require early recognition and instigation of treatment leading to better patient's outcomes.
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Currently, there is an unmet need to manufacture nanomedicines in a continuous and controlled manner. Three-dimensional (3D) printed microfluidic chips are an alternative to conventional PDMS chips as they can be easily designed and manufactured to allow for customized designs that are able to reproducibly manufacture nanomedicines at an affordable cost. The manufacturing of microfluidic chips using existing 3D printing technologies remains very challenging because of the intricate geometry of the channels. Here, we demonstrate the manufacture and characterization of nifedipine (NFD) polymeric nanoparticles based on Eudragit L-100 using 3D printed microfluidic chips with 1 mm diameter channels produced with two 3D printing techniques that are widely available, stereolithography (SLA) and fuse deposition modeling (FDM). Fabricated polymeric nanoparticles showed good encapsulation efficiencies and particle sizes in the range of 50-100 nm. SLA chips possessed better channel resolution and smoother channel surfaces, leading to smaller particle sizes similar to those obtained by conventional manufacturing methods based on solvent evaporation, while SLA manufactured nanoparticles showed a minimal burst effect in acid media compared to nanoparticles fabricated with FDM chips. Three-dimensional printed microfluidic chips are a novel and easily amenable cost-effective strategy to allow for customization of the design process for continuous manufacture of nanomedicines under controlled conditions, enabling easy scale-up and reducing nanomedicine development times, while maintaining high-quality standards.
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Introduction: Phalangeal microgeodic syndrome (PMS) is a rare disease of unknown etiology, which affects fingers and/or toes of children. Objectives: N/A Methods: N/AResults: Case Presentation The authors describe the case of a 9-year-old girl, who presented to the Pediatric Rheumatology outpatient clinic in November 2020 with painful swelling and cyanosis of all fingers for 3 weeks which had not improved with oral ibuprofen. She had no history of previous COVID-19 and, besides mild IgA vasculitis in 2015, was otherwise healthy. On physical examination, painful spindle-shaped swelling with functional limitation and cyanosis of fingers, associated with chilblain-like lesions were observed. She was started on pentoxifylline 400 + 200 mg/day and, later, nifedipine 0.5 mg/kg/day, and advised to avoid exposure to cold. Five months later she had marked improvement of pain and swelling, maintaining mild cyanosis. Laboratory workup revealed normal complete blood count, normal erythrocyte sedimentation and C-reactive protein, normal biochemical liver and renal parameters. Immunology tests showed normal IgG, IgA and IgM, positive antinuclear antibodies 1/100 and negative antidsDNA, ANCA, ACPA, rheumatoid factor, anti-ENA, anticentromere and antiphospholipd antibodies. Hand radiographs showed multiple small, round radiolucent images at the edge of the metaphysis of several phalanges. Hand MRI showed bone marrow edema in middle and distal phalanges of all fingers, and distal part of proximal phalanges (more diffuse and prominent in the second and fifth, bilaterally);there were no relevant changes in joints or tendons. These findings are compatible with PMS. Conclusion: This is a rare disease that should be included in the differential diagnosis of patients presenting with vascular acrosyndromes complaints. It can be misinterpreted as an infectious or post-infectious (namely COVID-19-related), inflammatory, or even malignant condition. It usually has a benign course and resolves with conservative treatment. Pediatric rheumatologists should be aware of this entity, as a timely and precise diagnosis prevents further investigations and complications.
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Introduction: Chilblain-like lesions have become a common complaint among children and adolescent during COVID-19 pandemic. A clear and objective relationship between this skin manifestation and SARS-CoV-2 infection has not been fully established neither its potential triggering rheumatologic disorders. Objectives: To characterize a group of children and adolescents with chilblain-like lesions. Methods: Data from out-patients of two northeast Italian hospitals were collected between December 2020 and April 2021. Clinical evaluation, blood test, interferon score and capillaroscopy were recorded in an electronic database. Results: We collected data from 35 patients, almost all adolescents (mean age: 13.1 years, 7 male and 28 females), with evidence of chilblain-like lesions. 5/35 had a parent who presented with COVID-19- related symptoms and/or with a positive swab test for SARS-CoV2 in the previous months. Only 2/35 had a positive swab test respectively three and four months before clinical evidence of chilblain-like lesions and none of those tested had a positive IgG serology. The average duration of the skin lesions, which appeared to be mainly localized to the toes, at the time of the first visit was 13.4 weeks. Two patients presented with signs of arthritis and tenosynovitis of the ankles. No other physical complaints were reported by the other patients. The most common capillaroscopic pattern was characterized by mild pericapillary oedema without hemorrhages or capillary abnormalities. No alterations in whole blood count and inflammatory markers were noted. 3/35 showed antinuclear antibodies in low counts. Interferon score was positive in 7 patients with a maximum of 10.1. (n.v. < 2.4) A trial of oral prednisone was the most common therapeutic approach in 17/35 patients. Three patients received Nifedipine and a course of hydroxychloroquine was started in those with severe complaints and a positive interferon score. Conclusion: Chilblain-like lesions presented as a benign clinical entity without a clear and objective proof of SARS-CoV2 contact in almost of the cases. All the investigations performed did not show any evidence of underlying systemic inflammation except for an enhanced interferon mediated response in some cases. We believe a strict follow-up of these cases is strongly warranted.
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As hypoxia is a major driver for the pathophysiology of COVID-19, it is crucial to characterize the hypoxic response at the cellular and molecular levels. In order to augment drug repurposing with the identification of appropriate molecular targets, investigations on therapeutics preventing hypoxic cell damage is required. In this work, we propose a hypoxia model based on alveolar lung epithelial cells line using chemical inducer, CoCl2 that can be used for testing calcium channel blockers (CCBs). Since recent studies suggested that CCBs may reduce the infectivity of SARS-Cov-2, we specifically select FDA approved calcium channel blocker, nifedipine for the study. First, we examined hypoxia-induced cell morphology and found a significant increase in cytosolic calcium levels, mitochondrial calcium overload as well as ROS production in hypoxic A549 cells. Secondly, we demonstrate the protective behaviour of nifedipine for cells that are already subjected to hypoxia through measurement of cell viability as well as 4D imaging of cellular morphology and nuclear condensation. Thirdly, we show that the protective effect of nifedipine is achieved through the reduction of cytosolic calcium, mitochondrial calcium, and ROS generation. Overall, we outline a framework for quantitative analysis of mitochondrial calcium and ROS using 3D imaging in laser scanning confocal microscopy and the open-source image analysis platform ImageJ. The proposed pipeline was used to visualize mitochondrial calcium and ROS level in individual cells that provide an understanding of molecular targets. Our findings suggest that the therapeutic value of nifedipine may potentially be evaluated in the context of COVID-19 therapeutic trials.
Subject(s)
COVID-19 , Nifedipine , A549 Cells , Calcium , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Cell Death , Humans , Hypoxia/drug therapy , Nifedipine/pharmacology , SARS-CoV-2 , SuperoxidesABSTRACT
The saponin glycyrrhizin from liquorice root shows the ability to enhance the therapeutic activity of other drugs when used as a drug delivery system. Due to its amphiphilic properties, glycyrrhizin can form self-associates (dimers, micelles) and supramolecular complexes with a wide range of hydrophobic drugs, which leads to an increase in their solubility, stability and bioavailability. That is why the mechanism of the biological activity of glycyrrhizin is of considerable interest and has been the subject of intensive physical and chemical research in the last decade. Two mechanisms have been proposed to explain the effect of glycyrrhizin on drug bioavailability, namely, the increase in drug solubility in water and enhancement of the membrane permeability. Interest in the membrane-modifying ability of glycyrrhizic acid (GA) is also growing at present due to its recently discovered antiviral activity against SARS-CoV-2 Bailly and Vergoten (2020) [1]. In the present study, the passive permeability of the DOPC lipid membrane for the calcium channel blocker nifedipine was elucidated by parallel artificial membrane permeability assay (PAMPA) and full atomistic molecular dynamics (MD) simulation with free energy calculations. PAMPA experiments show a remarkable increase in the amount of nifedipine (NF) permeated with glycyrrhizin compared to free NF. In previous studies, we have shown using MD techniques that glycyrrhizin molecules can integrate into the lipid bilayer. In this study, MD simulation demonstrates a significant decrease in the energy barrier of NF penetration through the lipid bilayer in the presence of glycyrrhizin both in the pure DOPC membrane and in the membrane with cholesterol. This effect can be explained by the formation of hydrogen bonds between NF and GA in the middle of the bilayer.
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AIMS: Hypertension is a common comorbidity of patients with COVID-19, SARS or HIV infection. Such patients are often concomitantly treated with antiviral and antihypertensive agents, including ritonavir and nifedipine. Since ritonavir is a strong inhibitor of CYP3A and nifedipine is mainly metabolized via CYP3A, the combination of ritonavir and nifedipine can potentially cause drug-drug interactions. This study provides guidance on nifedipine treatment during and after coadministration with ritonavir-containing regimens, using a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) analysis. METHODS: The PBPK/PD models for 3 formations of nifedipine were developed based on the Simcyp nifedipine model and the models were verified using published data. The effects of ritonavir on nifedipine exposure and systolic blood pressure (SBP) were assessed for instant-release, sustained-release and controlled-release formulations in patients. Various nifedipine regimens were investigated when coadministered with or without ritonavir. RESULTS: PBPK/PD models for 3 formulations of nifedipine were successfully established. The predicted maximum concentration (Cmax ), area under plasma concentration-time curve (AUC), maximum reduction in SBP and area under effect-time curve were all within 0.5-2.0-fold of the observed data. Model simulations showed that the inhibitory effect of ritonavir on CYP3A4 increased the Cmax of nifedipine 17.92-48.85-fold and the AUC 63.30-84.01-fold at steady state and decreased the SBP by >40 mmHg. Thus, the combination of nifedipine and ritonavir could lead to severe hypotension. CONCLUSION: Ritonavir significantly affects the pharmacokinetics and antihypertensive effect of nifedipine. It is not recommended for patients to take nifedipine- and ritonavir-containing regimens simultaneously.
Subject(s)
COVID-19 Drug Treatment , HIV Infections , Antiviral Agents/therapeutic use , Area Under Curve , Drug Interactions , HIV Infections/drug therapy , Humans , Models, Biological , Nifedipine/pharmacology , Nifedipine/therapeutic use , Ritonavir/pharmacology , SARS-CoV-2ABSTRACT
Amid efforts to care for the large number of patients with coronavirus disease (COVID-19), there has been considerable speculation about whether the lung injury seen in these patients is different than acute respiratory distress syndrome from other causes. One idea that has garnered considerable attention, particularly on social media and in free open-access medicine, is the notion that lung injury due to COVID-19 is more similar to high-altitude pulmonary edema (HAPE). Drawing on this concept, it has also been proposed that treatments typically employed in the management of HAPE and other forms of acute altitude illness-pulmonary vasodilators and acetazolamide-should be considered for COVID-19. Despite some similarities in clinical features between the two entities, such as hypoxemia, radiographic opacities, and altered lung compliance, the pathophysiological mechanisms of HAPE and lung injury due to COVID-19 are fundamentally different, and the entities cannot be viewed as equivalent. Although of high utility in the management of HAPE and acute mountain sickness, systemically delivered pulmonary vasodilators and acetazolamide should not be used in the treatment of COVID-19, as they carry the risk of multiple adverse consequences, including worsened ventilation-perfusion matching, impaired carbon dioxide transport, systemic hypotension, and increased work of breathing.