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Lung cancer is the leading cause of cancer related deaths worldwide, with a relatively low 5-year survival rate. Although there are some therapies against lung cancer, new effective treatment options are urgently required. Recently during the COVID-19 pandemic, we have seen that SARSCoV-2 binds to its receptor angiotensin-converting enzyme 2 (ACE2) via spike S1 to enter the cells. This study underlines the importance of SARS-CoV-2 spike S1 in inducing death in human lung cancer cells. Interestingly, we have seen that recombinant spike S1 treatment at very low doses led to death of human A549 lung cancer cells. On the other hand, boiled recombinant SARS-CoV-2 spike S1 remained unable to induce death, suggesting that the induction of cell death in A549 cells was due to native SARS-CoV-2 spike S1 protein. SARS-CoV-2 spike S1-induced A549 cell death was also inhibited by neutralizing antibodies against spike S1 and ACE2. Moreover, our newly designed wild type ACE2-interacting domain of SARS-CoV-2 (wtAIDS), but not mAIDS, peptide also attenuated SARS-CoV-2 spike S1-induced cell death, suggesting that SARS-CoV-2 spike S1- induced death in lung cancer cells depends on its interaction with ACE2 receptor. Similarly, recombinant spike S1 treatment also led to death of H1299 and H358 human lung cancer cells. Finally, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) intoxication led to the formation tumors in lungs of A/J mice and alternate day intranasal treatment with low dose of recombinant SARS-CoV-2 spike S1 from 22-weeks of NNK insult (late stage) led to induced apoptosis and tumor regression in the lungs. These studies indicate that recombinant SARS-CoV-2 Spike S1 protein may have implications in the treatment of lung cancer.
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Recent advancements in nanotechnology have resulted in improved medicine delivery to the target site. Nanosponges are three-dimensional drug delivery systems that are nanoscale in size and created by cross-linking polymers. The introduction of Nanosponges has been a significant step toward overcoming issues such as drug toxicity, low bioavailability, and predictable medication release. Using a new way of nanotechnology, nanosponges, which are porous with small sponges (below one microm) flowing throughout the body, have demonstrated excellent results in delivering drugs. As a result, they reach the target place, attach to the skin's surface, and slowly release the medicine. Nanosponges can be used to encapsulate a wide range of medicines, including both hydrophilic and lipophilic pharmaceuticals. The medication delivery method using nanosponges is one of the most promising fields in pharmacy. It can be used as a biocatalyst carrier for vaccines, antibodies, enzymes, and proteins to be released. The existing study enlightens on the preparation method, evaluation, and prospective application in a medication delivery system and also focuses on patents filed in the field of nanosponges.Copyright © 2023 The Authors.
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Background/Objectives: Rosmarinus Officinalis L.(Rosemary) extract Carnosic acid(CA) has been investigated for its antimicrobial and antioxidative properties(1). Only limited number of publications reported the utilization of this extract in SARSCoV-2 infection. Also, the mechanistic understanding of CA remains to be determined. Our goal was to elucidate the potential role of CA in COVID19. To obtain mechanistic insight of pharmacogenomic action of CA, comprehensive in silico analyses were performed. Further in vitro experiments were done to illustrate the cytotoxicity of CA and confirm in silico findings. Method(s): CA was extracted from Rosmarinus Officinalis L. by HPLC. Stimulation assays were performed using the COVID19 samples. In silico pharmacogenomic properties of CA were performed by using SwissADME. SwissTargetPrediction tool was utilized to define the possible targets. SARS-CoV-2-interacting proteins were evaluated using STRING(2). To verify in silico findings, gene expression levels were analyzed using qPCR. Result(s): Among the top 15 SwissTargetPrediction target molecules(out of 100), Prostaglandin E synthase(PTGES) had the highest probability for CA. Among 332 proteins identified using the STRING, PGES2 was found to be interacting with the nsp7, important molecule for viral replication. The stimulation assays and gene expression analyses confirmed the viral inhibitory role of CA through PTGES pathway. Conclusion(s): To our knowledge, our work is the first to reveal the inhibitory role of CA in COVID19 through PTGES pathway. Given the crucial role of PTGES in inflammation, it is noteworthy to examine CA as potential anti-SARS-CoV2 therapeutics.
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Introduction: Catatonia is a syndrome of primarily psychomotor disturbances most common in psychiatric mood disorders but that also rarely has been described in association with cannabis use. Case Presentation: A 15-year-old White male presented with left leg weakness, altered mental status, and chest pain, which then progressed to global weakness, minimal speech, and a fixed gaze. After ruling out organic causes of his symptoms, cannabis-induced catatonia was suspected, and the patient responded immediately and completely to lorazepam administration. Discussion(s): Cannabis-induced catatonia has been described in several case reports worldwide, with a wide range and duration of symptoms reported. There is little known about the risk factors, treatment, and prognosis of cannabis-induced catatonia. Conclusion(s): This report emphasizes the importance of clinicians maintaining a high index of suspicion to accurately diagnose and treat cannabis-induced neuropsychiatric conditions, which is especially important as the use of high-potency cannabis products in young people increases.Copyright © 2023, State Medical Society of Wisconsin. All rights reserved.
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Introduction: Bupivacaine is a local anesthetic which has been increasingly used in the post-operative state for pain control. Hepatotoxicity is a rare complication, and few cases are reported in patients with chronic liver disease. We present a case of acute liver injury from bupivacaine use in a healthy patient without prior history of liver disease. Case Description/Methods: A 68-year-old female with a past medical history of primary hypertension and recent nontraumatic complete tear of the right rotator cuff, presents to the hospital with fatigue, loss of appetite, and nausea. She recently underwent an arthroscopy of the right shoulder with repair of the rotator cuff two weeks prior. Her surgery was uncomplicated, and patient was started on bupivacaine ONQ pump infusion at 5 ml/hr for three days for post-operative pain. Further history reveals patient is non-alcoholic without prior liver disease, including cirrhosis. Review of systems is concerning for associated generalized abdominal discomfort. Physical exam demonstrated jaundice with scleral icterus with mild periumbilical tenderness to palpation without hepatosplenomegaly or ascites. Labs demonstrated elevated total bilirubin of 10.2 mg/dL with Alkaline phosphatase, ALT, and AST being 924 U/L, 429 U/L, and 279 U/L, respectively. Imaging studies including CT abdomen and pelvis with contrast, abdominal ultrasound, MRCP, and portal vein doppler were negative. Additional work up for underlying liver disease including acetaminophen and ethanol levels, SARS-CoV2, Hepatitis panel, EBV antigen, and urine toxicology were negative. It was determined patient had bupivacaine induced hepatotoxicity. Patient's health improved with conservative management and she was discharged with instructions for close monitoring of her LFTs. Discussion(s): Bupivacaine is an amino-amide anesthetic which binds to the intracellular portion of voltage-gated sodium channels and prevents depolarization of pain signals. It is metabolized by the liver and thus reports of hepatotoxicity, although rare, occur in patients with underlying liver pathology. Our patient became symptomatic with acute rise in LFTs. An extensive workup for other etiologies of acute liver toxicity was negative. Rapid vascular uptake of the drug is the most common reason for bupivacaine toxicity;and this remains a possibility for the mechanism of toxicity in our patient. A prior case report of bupivacaine hepatotoxicity demonstrated a cholestatic pattern, which is consistent with our findings.
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Introduction: Hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS), is a clinical syndrome characterized by hepatomegaly, right-upper quadrant pain, and ascites that occurs most commonly in the setting of high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT). The diagnosis can be confirmed on biopsy. Cemiplimab is an immune checkpoint inhibitor recently approved for the treatment of cutaneous squamous cell carcinoma. There are currently no known reports of immune checkpoint inhibitor-related VOD/SOS. Case Description/Methods: A 58-year-old female with a history of locally advanced basal cell carcinoma of the left eye treated with six months of Cemipilimab presented with ascites. On admission, labs were notable for a total bilirubin of 1.2, mildly elevated liver function tests, alkaline phosphatase 884, and international normalized ratio 2.1. A diagnostic tap revealed a high SAAG ascites that was negative for infection. A comprehensive serological workup for viral, metabolic and autoimmune causes was unrevealing. A transjugular liver biopsy demonstrated a hepatic venous pressure gradient of 18mmHg, nodular regenerative hyperplasia (NRH), and portal venopathy. The patient was discharged on steroids but returned one month later for recurrent ascites and worsening bilirubin to 12.6 (direct 7.3);COVID PCR was negative. A full rheumatologic and vasculitis workup was unremarkable. Repeat biopsy (Figure 1) demonstrated moderate NRH changes, prominent central vein sclerosis with fibrous obliteration, signs of SOS/ VOD and central venulitis with fibrotic changes with sinusoidal portal hypertension. Discussion(s): VOD occurs most often with hematopoietic stem cell transplantation, and chemotherapeutic agents. Here we present the first case of checkpoint inhibitor-induced VOD/SOS. Despite discontinuation of the offending agent and a trial of steroids, the patient's clinical course continued to deteriorate. She eventually developed refractory ascites and portosystemic encephalopathy. She was deemed not a candidate for liver transplant given her underlying malignancy. She was transitioned to home hospice before further treatment, such as Defibrotide could have been pursued. VOD associated with immune checkpoint inhibition should be considered in the differential of patients who develop new onset liver dysfunction and ascites while receiving these medications (Figure Presented).
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The novel SARS-CoV-2 virus known to cause the COVID-19 outbreak has resulted in a global healthcare crisis that has persisted the past 3 years. Thus, understanding the mechanisms underlying this disease are vital at this time. While there are issues of research infrastructure to handle the virus and because of the refractoriness of rodents to this disease, the availability of these tools is still limited. The cytokine storm and fatality presented in patients with severe COVID-19 can be mimicked with Staphylococcal enterotoxin B (SEB)-induced Acute Respiratory Distress Syndrome (ARDS). Within ~7 days, the survival rate drops to 0% for C3H/HeJ mice exposed to a dual dose of SEB. In this study, we administered cannabidiol (CBD) intraperitoneally for 3 days pre- and post-SEB dosing and found that the clinical outcomes improved significantly. Initial evaluation of scRNASeq data from lungs comparing naive to SEB-induced ARDS mice illustrated an increase in infiltrating immune cells, and a loss in pulmonary epithelial cells in the latter group. When evaluating the effect of CBD treatment on SEB-induced ARDS, we were able to demonstrate that CBD reduced the macrophage population. To characterize the mechanism by which CBD treatment ameliorated the inflammatory response, we found that CBD treated mice had significant reduction in infiltrating immune cells and alveolar thickening. This same histology and infiltration is presented in ARDS. MicroRNA expression analysis showed a significant increase in the expression mmu-miR-298-5p and mmu-miR- 566 with CBD treatment. Ingenuity Pathway Analysis (IPA) indicated that the dysregulated miRNAs were also implicated in pathways associated with macrophage activation, respiratory disease and inflammation, interferon stimulated genes, as well as genes which have been upregulated in the disease state of this model. These targets include but are not limited to Cebpb, Efhd2, Stat3, Socs3, Cxcl5, Gbp2, and Birc3. This finding offers insights for the development of preventive and therapeutic strategies in the treatment of ARDS, including that induced in COVID-19. Supported by NIH grants P01AT003961, P20GM103641, R01ES003961, R01AI129788, R01AI123947, R01AI160896 to MN and PSN and K99GM147910 to KW.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.
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Objective. To comparatively assess the early toxicity of treatment, its tolerability, 1-, 2-, 3-year overall survival, and local regional control rates in a group of patients receiving a radical cycle of accelerated or conventional fractionation chemoradiotherapy. Subjects and methods. The paper presents the interim results of a prospective study that included 115 patients with locally advanced cancer of the oropharynx, tongue root, and larynx who received a radical cycle of conformal chemoradiotherapy using accelerated (the single focal dose (SFD) was 2.4 Gy for 25-26 fractions) or conventional (SFD was 2.0 Gy for 32-33 fractions) fractionation in the period from 2015 to 2020. Results. An analysis comparing the study group with the control one revealed no statistically significant differences in the level of early toxicity of treatment (p=0.41). Complete tumor reversal was achieved in 57 (86.3%) patients in the study group and in 39 (79.5%) in the comparison group (p=0.23). The 1-, 2-, and 3-year local regional control rates in the accelerated fractionation group was 78.3+/-5.3%;65.9+/-6.8%, and 54.5+/-9.2%, respectively. The 3-year overall survival rate was 80.4+/-7.4%. These rates did not differ statistically from those in the conventional radiotherapy group (p=0.12-0.82);53 (80.3%) patients in the study group and 37 (75.5%) in the standard fractionation group received a radiation cycle without a forced interval. The treatment interval in the patients of both groups reduced the 2-year local regional control rates by 30.2% compared to that in the continuous cycle group (p=0.02). Conclusion. Accelerated fractionation chemoradiotherapy (SFD was 2.4 Gy for 25-26 fractions, the daily focal dose was 60.0- 62.4 Gy) is a procedure comparable with conventional radiation in its direct efficiency and safety. During the COVID-19 pandemic, this regimen can be considered to be a mainstay for patients with locally advanced oropharyngeal cancer in order to preserve the previous volumes of specialized healthcare.Copyright © A.V. SEMENOV I.A. GULIDOV O.G. LEPILINA M.U. RADZHAPOVA F.E. SEVRYUKOV K.B. GORDON.
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Background: Although mRNA SARS-CoV-2 vaccines have received emergencyuse- authorization for infants age 6 months and older, vaccine uptake is slow, stressing that questions of safety and durability of vaccine efficacy remain prominent. Method(s): Infant rhesus macaques (RMs) (n=8/group) at 2 months of age, comparable to human toddler age, were immunized intramuscularly at weeks 0 and 4 with 30mug stabilized prefusion SARS-CoV-2 S-2P spike (S) protein (Washington strain) encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or 15mug S protein mixed with 3M-052 in stable emulsion (Protein). At 1 year, vaccinated and age-matched unvaccinated RM (n=8) were challenged intranasally (106pfu) and intratracheally (2x106pfu) with B.1.617.2. Lung radiographs and pathology were blindly assessed, viral N gene RNA (vRNA) copies were measured by qPCR in pharyngeal swabs and lung, and neutralizing antibody and peripheral blood T cell responses were measured. Result(s): At 1 year, D614G-specific neutralizing antibody (nAb) titers were still detectable in the Protein (ID50=755;range: 359-1,949) and mRNA-LNP groups (ID50=73;range: 41-240). Both vaccines also induced cross-neutralizing antibodies to B.1.617.2. Peripheral blood CD4+ T cell responses to the ancestral spike protein at week 52 did not differ between the groups. However, median CD8+ T cell responses were higher (p=0.002, Mann Whitney) in the mRNA-LNP group (2.8%;range: 0.9%-7.1%) compared to the Protein group (0.8%;range: 0.1%-1.6%). Control RMs had significantly higher median vRNA copies/ml (1.4+/-2.7x108) in day 4 pharyngeal swabs compared to Protein (3.8+/-6.8x103) or mRNA-LNP (4.4+/-9.7x105) vaccinated RMs. Severe lung pathology was observed in 7 of 8 controls compared to 1 of 8 or 0 of 8 RMs in the mRNA-LNP or Protein group respectively. Protection against lung inflammation was associated with nAb titers (r=-0.592, p=0.003) (Figure 1). Conclusion(s): These results demonstrate that despite lower vaccine doses compared to adults, both protein and mRNA vaccines were safe, induced durable immune responses and provided comparable protective efficacy against infection with a heterologous SARS-CoV-2 variant in infants, implying that early life vaccination of human infants may lead to durable immunity. Neutralizing ID50 antibody titers are a correlate of protection in infant RMs challenged with SARS-CoV-2.
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Background: Next-generation SARS-CoV-2 vaccines demonstrated that nanoparticle messenger ribonucleic acid (mRNA) delivery is effective and safe for in vivo delivery in humans. Current treatments for cystic fibrosis (CF) primarily focus on modulator drug therapies designed to correct malfunctioning CF transmembrane conductance regulator (CFTR) protein, but these modulators are ineffective for the 10% of people with CF with variants that do not allow protein production. Among these is the splice variant 3120 + 1G >A, the most common CF-causing mutation in native Africans. Gene editing would allow production of CFTR protein and enhancement of function using available CFTR modulators. We have demonstrated that electroporation of a modified CRISPR-Cas9 base editor to primary human bronchial epithelial cells carrying 3120 + 1G >A and F508del mutant alleles achieved 75% genome editing of the splice variant, resulting in approximately 40% wild-type (WT) CFTR function [1]. Here,we evaluate the effectiveness of several new nanoparticle formulations at delivering green fluorescent protein (GFP) mRNA to CF bronchial epithelial (CFBE41o-) cells. Using the optimal formulation,we then tested the efficacy correction of the 3120 + 1G >Avariant in a CFTR expression minigene (EMG) integrated into the genome of isogenic CFBE cells using mRNA and plasmid deoxyribonucleic acid (DNA) encoding adenine base editor (ABE) and guide (g)RNA. Method(s): GFP served as a reporter to evaluate transfection efficiency, cell viability, and mean fluorescence intensity (MFI) for three dosages (150, 75, 32.5 ng of mRNA), four polymer-to-mRNA to weight (w/w) ratios (60, 40, 30, 20), and four polymers (R, Y, G, B). 7-AAD served as a live/dead stain to quantify viability, with flow cytometry results analyzed using FlowJo software. CFBE cells stably expressing the 3120 + 1G >A EMG were transfected with the optimized nanoparticle formulation to deliver ABE and gRNA at two dosages (150, 75 ng) of mRNA and DNA. CFTR function in CFBE cellswas measured by short circuit current, forskolin stimulation, and inh-172 inhibition as a measure of editing efficiency. Result(s): Flow cytometry showed that polymer R achieved more than 85% GFP transfection, compared with a maximum of approximately 35% for the other three polymers at the maximum 150-ng dose, with approximately 80% viability normalized to untreated cells. In addition, polymer R achieved GFP MFI more than one order of magnitude as high as other formulations (~30 000 vs 2700 MFI) for the other three polymers at 150-ng dose and 40 w/w ratio. CFBE cells transfected with polymer R nanoparticles containing ABE and guide RNA at 75 ng and 150 ng showed mean CFTR function increase to 10 muA 6 (standard error of the mean [SEM] 1.1 muA) (~10% of WT) and 6.3 muA (SEM 0.9 muA) (~6% of WT), respectively. Greater toxicity at the higher dose could explain the larger increase in CFTR current at the lower dose. DNA-encoded ABE plasmid and gRNA showed a less robust increase in CFTR function (2.9 muA [SEM 0.4 muA] for 75-ng dose;3.0 muA [SEM 0.4 muA] for 150-ng dose), which was probably a result of the nanoparticle formulation being optimized for RNA instead of DNA cargo or the additional intracellular barriers that must be overcome for successful DNA delivery. Conclusion(s): We demonstrated that an optimized nanoparticle formulation containing ABE and gRNA can correct splicing of isogenic cells bearing the 3120 + 1G >A CFTR variant, resulting in recovery of CFTR function. In ongoing work, we are adapting these nanoparticles for RNA- and DNAencoded ABE and gRNA delivery to primary human bronchial epithelial cells.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved
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Background: With the COVID-19 vaccine now available, there have been occasional reports of post-vaccination neurological complications. Case presentation: In this report, we present a case of neuromyelitis optica spectrum disorder (NMOSD) that developed one month after the patient received the second dose of BIBP COVID-19 vaccine (SARS-CoV-2-Vaccine [Vero Cell] Inactivated). The patient presented with itching, numbness in the hand and right side of the face, as well as nausea, vomiting, and hiccups. Brain MRI revelead lesions in the area postrema, medulla, and bilateral hypothalamus, which are typical of NMOSD. Serum antibodies to anti-AQP4 and anti-MOG were negative. Conclusion(s): The pathogenesis of NMOSD development after vaccination is still unknown. NMOSD is generally aggressive and disabling, it is important for the neurologist to be attentive to the highly variable clinical presentation after COVID-19 vaccination for early diagnosis and effective treatment.Copyright © 2023
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Pulmonary parenchymal involvement secondary to the subcutaneous injection of silicone gels is an unusual condition which occurs more frequently in women aged between 22 and 55 years. Although different theories have been put forward about its etiology, it is unknown and the condition may cause local and systemic complications and even have a fatal outcome. Few cases have been reported in South America and there is no report of this unique entity in Peru. We present the case of a previously healthy 28-year-old male transgender patient who, after an illegal subcutaneous injection of silicone gels in the gluteal region given by a non-healthcare professional, showed progressive respiratory distress and stabbing chest pain of approximately 7 out of 10 on the pain scale within the first 24 hours. Upon admission to the emergency room, respiratory failure was objectively evidenced since the patient had an oxygen saturation of 72 % at a FiO2 of 21 %, as well as pulmonary parenchymal involvement both in the CT scan and chest X-ray with signs highly suggestive of this pathology. Using a SARS-CoV-2 RNA real-time RT-PCR test performed on a respiratory specimen, COVID pneumonia, immunodeficiency disorders and pulmonary embolism were ruled out. Since there is no standard treatment, the patient was given relevant support measures such as the administration of supplemental oxygen at a low flow rate by binasal cannula, intravenous systemic corticosteroids and antibiotic therapy, thus achieving good progress with resolution of the initial clinical presentation. Then, after 10 days of intrahospital treatment, the patient was discharged.Copyright © La revista. Publicado por la Universidad de San Martin de Porres, Peru.
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Introduction: Use of hematopoietic cell transplantation (HCT) in patients with trisomy 21 (+21) is infrequent given concerns about increased toxicity with cytotoxic chemotherapy.1 Due to increasing evidence of benefit from post-HCT cyclophosphamide (PTCy) for graft-vs.-host disease (GVHD) prophylaxis and lack of prior descriptions in patients with +21,2-4 we report on 2 patients with +21 and acute lymphoblastic leukemia (ALL) who underwent HCT with PTCy. Method(s): Retrospective data were collected from 2 patients with ALL and +21 who underwent allogeneic HCT with PTCybased GVHD prophylaxis from 2019 to 2021. Data collected included age, disease risk, HCT-CI, GVHD incidence, and survival. Result(s): Patient 1 is a 22-year-old male and patient 2 a 25-year-old female. Both had Ph-negative, B-cell ALL. Patient 1 had ETV6/RUNX1 rearrangement, del 12p, gain of X, and he had recurrence of measurable residual disease (MRD) after initial MRD-negative CR with two lines of therapy pre-HCT. Patient 2 had normal cytogenetics and relapsed disease with 4 prior lines of therapy. Both achieved MRD-negativity pre-HCT. Both received fludarabine and melphalan conditioning, and patient 1 also received thiotepa 2.5 mg/kg. PTCy was given on days +3 and 4 at 50 mg/kg with sirolimus and tacrolimus for GVHD prophylaxis. Patient 1 had a haploidentical donor and received one dose of rabbit ATG (1 mg/kg) on day +5. Patient 2 had a matched unrelated donor. There was no significant delay in engraftment of ANC (day 16-19) or platelets (day 15-16). Patient 2 developed acute GVHD at day 30 (stage I skin, stage II GI) that resolved with steroids which were tapered off by day 96 without recurrence. Sirolimus stopped at day 79 (pt 1) and 103 (pt 2) and tacrolimus was stopped at day 274 (pt 1) and 469 (pt 2). Patient 1 developed a sirolimus-induced pericardial effusion at day 84 which did not recur after sirolimus discontinuation. Patient 2 developed moyamoya 8 months post-HCT during tacrolimus taper without other GVHD symptoms. Response to steroids was noted, so tacrolimus was restarted for residual neurological deficit. Neither patient developed chronic GVHD or left ventricular ejection fraction decline, and neither patient had disease relapse at follow-up of 30 and 16 months respectively. Patient 2 developed COVID pneumonia 16 months post-HCT and died while in CR. Patient 1 remains alive, in CR, and off immunosuppression nearly 3 years post HCT. Conclusion(s): Allogeneic HCT with PTCy at standard doses did not appear prohibitively toxic in patients with +21 when administered after reduced-intensity conditioning. In this case series, GVHD rates seemed consistent with larger series in patients without +21. Moyamoya development is associated with autoimmunity in patients with +21 and hence may have been GVHD-related5. Trisomy 21 should not be a barrier to patients otherwise eligible for HCT, even with PTCy prophylaxis.Copyright © 2023 American Society for Transplantation and Cellular Therapy
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Correlation between the BOD/COD ratio and Partition coefficient of octanol/ water (Pow) on a single organic substance shows that the Pow value is directly proportional to the toxicity level and inversely proportional to BOD/COD ratio. This research examined the correlation to a mixture of organic substances. The objective is to obtain a varied range of substances, as well as determining the quality of wastewater discharging to fresh waters. Need for analysis of organic substances used as antiseptics during the Covid-19 pandemic. In addition, organic substances from the organophosphate pesticide class, diazinon, were used. BOD5, COD, Pow, and LC50-96h toxicity tests using Daphnia magna were used. Six types of the mixture of organic substances included diazinon-formaldehyde-isopropyl alcohol, ethanol-oxalic acid-formaldehyde, isopropyl alcohol-glycerol-lactose, acetic acid-isopropyl alcohol-formaldehyde, sucrose-glycerol-acetic acid, and oxalic acid-formaldehyde-diazinon, with 3 different concentrations of 10, 100, and 1000 mg/L, three repetitions. The lowest BOD/COD ratio (<0.2) and the highest Pow value (>4) are found in diazinon-formaldehyde-IPA. Its toxicity in D. magna also showed the lowest LC-50 (11.82 mg/L). Whereas, sucrose-glycerol-acetic acid had the highest BOD/COD ratio (>0.7) and lowest Pow (<0.7) with the highest LC-50 (567.88 mg/L). Other organic substances mixtures have characteristics in the range of these mixtures. Pow variability and the BOD/COD ratio have a negative correlation. A mixture of organic matter is more biodegradable making it has a higher tendency to dissolve in water.Copyright © 2022 Informatics Publishing Limited and The Society of Toxicology. All rights reserved.
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Objective: To analyze the clinical characteristics of fatal cardiac adverse events associated with chloroquine, which was recommended for the antiviral treatment of novel coronavirus pneumonia, and provide reference for clinical safe drug use. Method(s): The fatal cardiac adverse events associated with chloroquine were searched from the World Health Organization global database of individual case safety reports (VigiBase). The clinical characteristics of the individual cases with well-documented reports (VigiGrade completeness score >=0.80 or with detailed original reports) were analyzed. The adverse events were coded using the systematic organ classification (SOC) and preferred term (PT) of Medical Dictionary for Regulatory Activities (MedDRA) version 22.1 of International Conference on Harmonization (ICH). Result(s): Up to 23 February 2020, a total of 45 reports of fatal heart injuries related to chloroquine were reported in VigiBase, which were from 16 countries. Of them, 30 reports were fully informative. Among the 30 reports,20 cases developed fatal cardiac adverse events after a single large dose of chloroquine. Of them, 17 cases' fatal cardiac adverse events were caused by overdose of chloroquine (15 cases were suicide or suspected suicide, and 2 children took chloroquine by mistake);3 cases' fatal cardiac adverse events were caused in clinical treatment;18 cases showed arrhythmia and cardiac arrest;6 cases showed prolonged QRS wave or QT interval;6 cases were with hypokalemia, including 4 severe ones. Among the 30 reports, 10 cases developed fatal cardiac adverse events after multiple administration of chloroquine, of which 4 cases were treated with chloroquine for 23 days to 2 months and died of heart failure, cardiac arrest or myocardial infarction;6 cases were treated with chloroquine for 20 months to 29 years and all of them had cardiomyopathy, which were confirmed by endomyocardial biopsy to be caused by chloroquine in 3 cases. Conclusion(s): Cardiac toxicity was the primary cause of fatal adverse events caused by chloroquine;the main manifestation of single large dose of chloroquine was arrhythmia and the manifestation of multiple administration was cardiomyopathy.Copyright © 2020 by the Chinese Medical Association.
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The coronavirus disease of 2019 (COVID-19) caused by SARS-CoV-2 virus led to a worldwide pandemic. Emergency use of an investigational medication, Paxlovid, was approved for patient 12 and older who tested positive for COVID-19 and at high risk for severe infection. Inflammatory Bowel Disease (IBD) is a chronic condition causing inflammation in the gastrointestinal tract. Ulcerative Colitis (UC) is a type of IBD centralized in colon and commonly treated with Immunosuppressive drugs. We present an adolescent with UC treated with paxlovid due to being on tacrolimus who developed with suspected tacrolimus toxicity. CASE REPORT: A 13-year-old female with UC presented to the ED with vomiting and fatigue after paxlovid ttreatment for COVID. The patient's UC treatment included tacrolimus along with ustekinumab. She had been diagnosed with SARS-CoV-2 and prescribed Paxlovid bid x 5 days due to immunosuppressive status. Tacrolimus was held during treatment. Once paxlovid completed, tacrolimus was restarted. Two days later, patient presented to ER for vomiting, fatigue, headaches and myalgia. Labs revealed a tacrolimus level of >60 ng/ml. Electrolytes and Creatinine were normal. Toxicology felt this was due to interaction between paxlovid and tacrolimus. Patient advised to hold tacrolimus for 48 hours and repeat levels were 15.8 ng/mL. Symptoms resolved and level repeated three days later and was 2.9 ng/mL. DISCUSSION: Tacrolimus is an immunosuppressant, commonly used for management of organ transplants but also been found effective in treatment of IBD. Tacrolimus requires close monitoring as toxicity may lead to acute or chronic kidney disease. The normal concentration is between 5-15 ng/mL. Due to rapid escalation of the COVID-19 pandemic, Paxlovid was approved for emergency use for treatment of high-risk patients. It is administered as a 5-day oral course consisting of nirmatrelvir and ritonavir. Our patient was prescribed Paxlovid due to risk secondary to immunosuppression. She was appropriately instructed to stop tacrolimus. Ritonavir is a cytochrome P450 3A inhibitor and can increase plasma concentration of tacrolimus. She restarted tacrolimus treatment 12 hours after her last dose of Paxlovid and presented with symptoms and a level consistent with toxicity. This level was concluded to be due to drug interaction between tacrolimus and Paxlovid. After further withholding of tacrolimus, symptoms improved, and levels normalized. Previous reports in transplant population stress importance of decreasing the dose of tacrolimus or withholding during the course of paxlovid treatment. This case demonstrates the importance of not only ceasing tacrolimus when administering paxlovid, but continuing discontinuation for longer period post completion of therapy to minimize interactions.Copyright © 2023
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Background: Since the introduction of COVID-19 vaccines, many reports have focused on adverse reactions. However, there is no global agreement on how to manage those patients. We aim to assess the management of adverse reactions by an immunoallergology department and its outcomes. Method(s): Retrospective analysis of the patients sent to our centre from January to October 2021 for adverse reactions to a COVID-19 vaccine, and who were considered ineligible for a 2nd dose by general practitioners. We collected data on the reported reactions, allergological study and outcomes. Result(s): 123 patients with adverse reactions were included (77% women, n = 95), mean age 55 years-old (min 12;max 92). Pfizer/ BioNTech Vaccine was inoculated in 64 patients (52%);Moderna in 15 (12%);AstraZeneca in 44 (36%). 65 patients (53%) presented symptoms compatible with allergic reactions: 86% (n = 56) with mucocutaneous symptoms, mainly urticaria-like lesions and/or angioedema;17% (n = 11) with suspected anaphylaxis and 5% (n = 3) with Steven-Johnson Syndrome. 19 patients performed skin testing with: PEG2000 (n = 17);polysorbate 80 (n = 15);COVID-19 vaccines (n = 21). Four patients had at least one positive test. 58 patients (47%) presented with non-allergic reactions. They showed great variability of symptoms. Most mild: 47% reported non-specific symptoms (such as malaise, headache, myalgia, fever, or fatigue) and 26% reported local reactions on the inoculation site. Some severe: 6 with deep vein or pulmonary thrombosis, 4 with myocarditis, 2 with stroke or myocardial infarction, and 1 with VITT. Patients with positive skin tests or severe previous reactions (n = 36, 29%) were referred for an alternative vaccine. Those with suspected allergic reaction but negative skin tests were premedicated with antihistamines before the 2nd dose. Follow-up showed: of the 81 patients (66%) who received an additional dose, 25% (n = 20) reported an adverse reaction, which was mild, and no case of anaphylaxis was reported. 16 (13%) refused a 2nd dose, and for 26 (21%) the information could not be obtained. Conclusion(s): The intervention of an allergologist had a significant positive impact on vaccination rates, with 2/3 of patients being reclassified as eligible for a 2nd dose. Allergological study and intervention identified vaccine-allergic patients and guided the decision on vaccine change and premedication, which resulted in a considerably lower number of adverse reactions to the 2nd dose, or at least its severity.
ABSTRACT
Background: COVID-19 virus vaccines are associated with adverse events. We aim to characterize and compare adverse reactions to different COVID-19 vaccines in a Portuguese centre. Method(s): Retrospective analysis of patients with adverse reactions to COVID-19 vaccines referred to our Immunoallergology Department between January and October 2021. The patients were divided according to the vaccine used: Pfizer/BioNTech (Pf), Moderna (M), or AstraZeneca (AZ). Result(s): 123 patients were included. 64 patients (52%) reacted to the Pf vaccine (77% women, mean age 49 years old);15 (12%) to the M vaccine (87% females, mean age 50 years old);and 44 (36%) to the AZ vaccine (75% women, mean age 64.8 years old). All groups showed a higher number of non-immediate reactions (>6h after inoculation): 59% for Pf, 60% for M, and 91% for AZ. Reactions to Pf and M were more frequently allergic-like (63% and 60%, respectively). Reactions to AZ were predominantly non-allergic (64%). The most frequently reported reactions for Pf and M were: sensation of throat tightness (Pf 31%, M 20%), urticaria (Pf 30%, M 27%), angioedema (Pf 17%, M 33%), constitutional non-specific symptoms (Pf 25%, M 27%), and local reactions on the inoculation site (Pf 20%, M 33%). There were 8 (13%) patients with suspected anaphylaxis with Pf, 3 (20%) with M, and none with AZ. The most frequently reported reactions for AZ were cardiovascular events (30%): myocardial, cerebral or pulmonary thromboembolic events (n = 6), phlebitis (n = 5), myocarditis (n = 1), and vaccine-induced immune thrombotic thrombocytopenia (n = 1). Other common reactions were constitutional non-specific symptoms (32%), local reactions on the inoculation site (18%), urticaria (23%), angioedema (14%), and non-urticaria rash (14%). Conclusion(s): Adverse reactions were more common in women. The mRNA vaccines were more frequently associated with allergic-like reactions, including anaphylaxis. In contrast, AZ vaccine was associated with nonallergic cardiovascular reactions. Up to 1/3 of patients in each group reported constitutional non-specific symptoms and local reactions on the inoculation site.
ABSTRACT
Background: Delayed-type cutaneous adverse reactions (DCARs) are potential adverse reactions induced by COVID-19 vaccinations. Objective(s): To investigate the immune pathomechanism of COVID-19 vaccination-related DCARs. Method(s): We conducted a prospective observational study on patients with COVID-19 vaccine-DCARs and tolerant subjects. Serum immune molecules and high-parameter blood cell analysis were analyzed.In vitro lymphocyte activation test (LAT) was performed to evaluate the causative allergens of COVID-19 vaccines for DCARs. Result(s): We enrolled 103 patients with COVID-19 vaccine-DCARs. Patients suffered from DCARs mainly after the first vaccination dose (75.7%). Compared to the tolerant controls, patients with DCARs showed significantly higher serum levels of IL-4, IL-6, IL-8, IL-17A, IL-18, IFN-gamma, IP-10, MIG, granulysin, PARC and TARC(P=3.40x10-5-0.028). High-parameter flow cytometric analysis revealed significant increased CD4+Th2, CD4+Th17, CD4+Th22, CD4+LAG-3+, CD4+CD103+Trm, Tfr, CD8+CXCR3+, CD8+Tc2, CD8+Tc17 and CD8+CTLA4+cell populations relative to total DCARs and specific phenotypes(P=0.001-0.042). In vitro LAT assays measuring IFN-gamma, granulysin, and granzyme B showed that patients with AZD1222-DCARs were significantly reactive to polysorbate 80 and spike protein;BNT162b2-DCARs were significantly reactive to polyethene glycol(PEG) 2000, and spike protein;while mRNA-1273-DCARs were significantly reactive to PEG 2000, tris and spike protein(P<0.05). Conclusion(s): We demonstrated a distinct immune response related to variable clinical phenotypes involved in the immune mechanism of COVID-19 vaccines-DCARs. In vivo LAT assays showed that COVID-19 vaccines excipients and spike protein were potential major components related to the COVID-19 vaccines-induced DCARs.Copyright © 2023