scholarly journals Follow Your Nose: A Key Clue to Understanding and Treating COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Christopher Edwards ◽  
Oleksandra Klekot ◽  
Larisa Halugan ◽  
Yuri Korchev
Keyword(s):  
Atp Release ◽  
Control Group ◽  
High Dose ◽  
Alveolar Cells ◽  
Cough Reflex ◽  
Angiotensin Converting Enzyme 2 ◽  
High Dose Dexamethasone ◽  
Nociceptive Stimulus ◽  
Angiopoietin 2 ◽  
Von Willebrand

This paper suggests that ATP release induced by the SARS-CoV-2 virus plays a key role in the genesis of the major symptoms and complications of COVID-19. Infection of specific cells which contain the Angiotensin-Converting Enzyme 2 (ACE2) receptor results in a loss of protection of the Mineralocorticoid Receptor (MR). Local activation by cortisol stimulates the release of ATP initially into the basolateral compartment and then by lysosomal exocytosis from the cell surface. This then acts on adjacent cells. In the nose ATP acts as a nociceptive stimulus which results in anosmia. It is suggested that a similar paracrine mechanism is responsible for the loss of taste. In the lung ATP release from type 2 alveolar cells produces the non-productive cough by acting on purinergic receptors on adjacent neuroepithelial cells and activating, via the vagus, the cough reflex. Infection of endothelial cells results in the exocytosis of WeibelPalade bodies. These contain the Von Willebrand Factor responsible for micro-clotting and angiopoietin-2 which increases vascular permeability and plays a key role in the Acute Respiratory Distress Syndrome. To test this hypothesis this paper reports proof of concept studies in which MR blockade using spironolactone and low dose dexamethasone (SpiDex) was given to PCR-confirmed COVID-19 patients. In 80 patients with moderate to severe respiratory failure 40 were given SpiDex and 40 conventional treatment with high dose dexamethasone (HiDex). There was 1 death in the HiDex group and none in the SpiDex. As judged by clinical, biochemical and radiological parameters there were clear statistically significant benefits of SpiDex in comparison to HiDex. A further 20 outpatients with COVID-19 were given SpiDex. There was no control group and the aim was to demonstrate safety. No adverse effects were noted and no patient became hyperkalaemic. 90% were asymptomatic at 10 days. The very positive results suggest that blockade of the MR can produce major benefit in COVID19 patients. Further larger controlled studies of inpatients and outpatients are required not only for SARS-CoV-2 infection per se but also to determine if this treatment affects the incidence of Long COVID.

Survey of the Side Effects of ITP Therapies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3327-3327 ◽  
Author(s):  
Charles W Shaffer ◽  
Naznin Haq ◽  
James B Bussel
Keyword(s):  
Side Effects ◽  
Board Of Directors ◽  
Side Effect ◽  
Research Funding ◽  
Control Sample ◽  
Control Group ◽  
High Dose ◽  
Advisory Committees ◽  
High Dose Dexamethasone ◽  
Equity Ownership

Abstract Abstract 3327 Introduction: Adult immune thrombocytopenia (ITP) is an autoimmune disorder characterized by an isolated low platelet count. Options for initial therapy in children and adults include corticosteroids (CS), intravenous immunoglobulin (IVIG), and anti-D. Second-line treatments include splenectomy, rituximab, and the thrombopoietin receptor agonists (TPO-A) eltrombopag and romiplostim. Treatments are usually effective in raising platelet counts, but there are often associated toxicities. We designed and administered a patient survey to compare side effects reported with different ITP therapies to an off treatment control group. Methods: A literature search identified 56 distinct side effects reported by patients on medical therapy for ITP. A self-report questionnaire was designed that asked patients how frequently (never, occasionally, regularly, almost always, always) they had experienced each side effect during the last 30 days. If a respondent had experienced the side effect, he/she was also asked to indicate the level of distress associated with the symptom on a rating scale. Adult non-pregnant patients with ITP were eligible for the IRB-approved study if they were currently taking one of the following therapies, and had done so for at least 30 days: CS, rituximab plus pulse high dose dexamethasone [Dex-Ritux], eltrombopag, IVIG, romiplostim, or no therapy (control group). Clinical details were obtained from patient records. Side effects in the treatment groups were compared to the control sample using the Wilcoxon rank-sum test (alpha = .05). Results: Ninety-one eligible patients completed the survey. Eleven (12%) were on CS (9 patients on prednisone [median dose 20mg/day] and 2 on pulse high dose dexamethasone), 11 (12%) on Dex-Ritux, 21 (23%) on eltrombopag, 9 (10%) on IVIG, 22 (24%) on romiplostim, and 17 (19%) on no therapy. Sixty-two percent overall and 71% of control patients were female (n=56, n=12). One hundred percent of patients reported experiencing at least one side effect. The most commonly reported side effects were fatigue (n= 78; 86%), stress (n=70; 77%), anxiety (n=56; 62%), joint pain (n=55; 60%), and muscle pain (n=55; 60%). Most side effects reported by patients on treatment did not occur with significantly greater frequency or distress than in the control sample. Side effects that occurred with significantly greater frequency compared to the control sample were found in every treatment group except eltrombopag. Most of these symptoms were mild and not associated with greater distress compared to control patients who experienced the same side effect. The number of side effects occurring with greater frequency was 15 with romiplostim, 5 with Dex-Ritux, 3 with CS, and 2 with IVIG. Side effects that occurred with significantly greater distress compared to the control sample were found in every treatment group. Greater distress was not necessarily associated with greater frequency (see Table). Many unwanted effects, such as fatigue, insomnia, dyspepsia, and skin irritation, that have traditionally been associated with CS treatment did not occur with greater frequency or distress in that group; however, few patients were on long term or high dose CS therapy. Surprisingly, unlike published series, we found that romiplostim patients experienced fatigue with significantly greater frequency and more distress than the control group (see Figure). Conclusion: These results suggest that, while unwanted effects of ITP treatment in adults are common, the great majority are not associated with significant patient distress. Patients who participated in this study were being treated at a clinic where treatment guidelines for adult ITP favored TPO-As over CS. Thus our findings may not reflect general experience. Disclosures: Bussel: Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shinogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Portola: Consultancy.

Long-Term Effect of High-Dose Dexamethasone with or without Low-Dose Dexamethasone Maintenance in Untreated Immune Thrombocytopenia

2014 ◽  
Vol 133 (1) ◽  
pp. 124-128 ◽  
Author(s):  
Banhe Din ◽  
Xingwen Wang ◽  
Yuye Shi ◽  
Yufeng Li
Keyword(s):  
Immune Thrombocytopenia ◽  
Low Dose ◽  
Overall Response Rate ◽  
Control Group ◽  
High Dose ◽  
High Dose Dexamethasone ◽  
Group 4 ◽  
Long Term Effect ◽  
Group 2

Background: To tackle the problems associated with high-dose dexamethasone (HD-DXM) in patients with immune thrombocytopenia (ITP). Aim: To compare the efficacy of HD-DXM with or without low-dose dexamethasone maintenance in untreated ITP patients. Results: Dexamethasone (40 mg/day) was given in 4-day pulses every 14 days for 3 cycles in 61 patients with ITP. Among them, 30 cases were given dexamethasone (0.035 mg/kg per day) for maintenance between pulsed HD-DXM and after 3 HD-DXM courses (HD-DXM-M group) and another 31 cases did not receive dexamethasone maintenance (HD-DXM-nM group). The control group comprised the patients who received prednisone (prednisone group). The following results were obtained: (1) at the end of the 3rd cycle, the overall response rate (ORR) was higher in the HD-DXM group than in the prednisone group; (2) the ORR of the HD-DXM group peaked after the 3rd cycle; (3) the ORR after each course was higher in the HD-DXM-M group than in the HD-DXM-nM group; (4) in the 12th month after HD-DXM discontinuation, the relapse rate of the HD-DXM-M group was lower than that of the other groups (prednisone and HD-DXM-nM). Conclusion: Treatment with 3 cycles of HD-DXM pulses with low-dose dexamethasone maintenance is an effective method for untreated ITP.

High dose dexamethasone increases circulating P-selectin and von Willebrand factor levels in healthy men

2005 ◽  
Author(s):  
Bernd Jilma ◽  
Tuende Cvitko ◽  
Astrid Winter-Fabry ◽  
Karin Petroczi ◽  
Peter Quehenberger ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
High Dose ◽  
Healthy Men ◽  
High Dose Dexamethasone ◽  
Von Willebrand ◽  
Willebrand Factor

Prophylactic effects of dexamethasone in lung injury caused by hyperoxia and hyperventilation

1992 ◽  
Vol 72 (4) ◽  
pp. 1320-1325 ◽  
Author(s):  
J. M. Davis ◽  
J. Whitin
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Tracheal Aspirate ◽  
Lung Compliance ◽  
Lung Damage ◽  
Control Group ◽  
High Dose ◽  
Albumin Concentration ◽  
High Dose Dexamethasone ◽  
Cell Counts

To determine if prophylactic corticosteroids would prevent acute lung injury caused by hyperoxia and barotrauma, 29 piglets (1.2 +/- 0.3 kg, 1–2 days of age) were studied. Ten piglets were hyperventilated [arterial PCO2 (PaCO2) 15–20 Torr] with 100% O2 for 48 h and compared with 10 piglets treated with the identical management but given 0.7 mg/kg of dexamethasone at time 0 and every 12 h for the 48-h study. Six piglets were normally ventilated (PaCO2 40–45 Torr) for 48 h with 21% O2 as an additional control group. Pulmonary function and tracheal aspirates were examined at time 0 and every 24 h. Bronchoalveolar lavage was performed for surfactant analyses at the conclusion of the study. In animals treated with hyperoxia and hyperventilation, lung compliance decreased 32% and tracheal aspirate polymorphonuclear leukocyte (PMN) chemotactic activity increased by 51%, cell counts by 204%, number of PMNs by 277%, elastase activity by 111%, and albumin concentration by 328% over 48 h (P less than 0.05). In contrast, dexamethasone-treated piglets had increases in only tracheal aspirate albumin concentration (206%) over the 48-h study. All cellular and biochemical variables were lower in dexamethasone-treated compared with hyperoxic hyperventilated piglets. Room air normal ventilation controls had only a 108% increase in tracheal aspirate albumin concentration noted. Despite quantitative differences in surfactant among the three groups, activity was unaffected. Results indicate that hyperoxia and hyperventilation for 48 h causes significant inflammatory changes and acute lung injury and that prophylactic high-dose dexamethasone significantly ameliorates this lung damage.

Acetaminophen: Neonatal hepatotoxicity due to late pregnancy exposure

1987 ◽  
Vol 45 ◽  
pp. 718-719
Author(s):  
G.A. Miranda ◽  
M.A. Arroyo ◽  
C.A. Lucio ◽  
M. Mongeotti ◽  
S.S. Poolsawat
Keyword(s):  
Low Dose ◽  
Fetal Liver ◽  
Late Pregnancy ◽  
Toxic Chemicals ◽  
Control Group ◽  
High Dose ◽  
Over The Counter ◽  
Liver And Kidney ◽  
Neonatal Liver ◽  
Childbearing Women

Exposure to drugs and toxic chemicals, during late pregnancy, is a common occurrence in childbearing women. Some studies have reported that more than 90% of pregnant women use at least 1 prescription; of this, 60% used more than one. Another study indicated that 80% of the consumed drugs were not prescribed, and of this figure, 95% were “over-the-counter” drugs. Acetaminophen, the safest of all over-the-counter drugs, has been reported to induce fetal liver necrosis in man and animals and to have abortifacient and embryocidal action in mice. This study examines the degree to which acetaminophen affects the neonatal liver and kidney, when a fatty diet is simultaneously fed to the mother during late pregnancy.Timed Swiss Webster female mice were gavaged during late pregnancy (days 16-19) with fat suspended acetaminophen at a high dose, HD = 84.50 mg/kg, and a low dose, LD = 42.25 mg/kg; a control group received fat alone.

Screening for haemorrhagic disorders in paediatric patients by means of a questionnaire

2009 ◽  
Vol 29 (S 01) ◽  
pp. S87-S89 ◽  
Author(s):  
I. Music ◽  
M. Novak ◽  
B. Acham-Roschitz ◽  
W. Muntean
Keyword(s):  
Predictive Value ◽  
Laboratory Diagnosis ◽  
Von Willebrand Disease ◽  
Control Group ◽  
Older Children ◽  
Mild Disease ◽  
History Of ◽  
Von Willebrand ◽  
Specific Symptoms ◽  
Infants And Young Children

SummaryAim: In children, screening for haemorrhagic disorders is further complicated by the fact that infants and young children with mild disease in many cases most likely will not have a significant history of easy bruising or bleeding making the efficacy of a questionnaire even more questionable. Patients, methods: We compared the questionnaires of a group of 88 children in whom a haemorrhagic disorder was ruled out by rigorous laboratory investigation to a group of 38 children with mild von Willebrand disease (VWD). Questionnaires about child, mother and father were obtained prior to the laboratory diagnosis on the occasion of routine preoperative screening. Results: 23/38 children with mild VWD showed at least one positive question in the questionnaire, while 21/88 without laboratory signs showed at least one positive question. There was a trend to more specific symptoms in older children. Three or more positive questions were found only in VWD patients, but only in a few of the control group. The question about menstrual bleeding in mothers did not differ significantly. Sensitivity of the questionnaire for a hemostatic disorder was 0.60, while specifity was 0.76. The negative predictive value was 0.82, but the positive predictive value was only 0.52. Conclusions: Our small study shows, that a questionnaire yields good results to exclude a haemostatic disorder, but is not a sensitive tool to identify such a disorder.

Significance of Platelet β-Adrenoceptors for Platelet Responses In Vivo and In Vitro

1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
Author(s):  
P T Larsson ◽  
N H Wallén ◽  
A Martinsson ◽  
N Egberg ◽  
P Hjemdahl
Keyword(s):  
Ex Vivo ◽  
High Dose ◽  
Platelet Aggregability ◽  
Adrenoceptor Agonist ◽  
Dose Infusion ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.

Employing Gamma Ray Irradiated Giardia lamblia as Trialed Vaccine in Experimental Animal

2019 ◽  
Vol 9 (02) ◽  
Author(s):  
Amal Kamil Abdul Sada ◽  
Amany Mohamed Al-Kaysi
Keyword(s):  
Giardia Lamblia ◽  
Gamma Ray ◽  
Age Groups ◽  
Active Phase ◽  
Study Groups ◽  
Negative Control ◽  
Control Group ◽  
High Dose ◽  
Histopathological Changes ◽  
Gamma Irradiated

This is an experimental trial to prepare a vaccine from gamma-irradiated Giardia lamblia which is evaluated in experimental animals. The study was conducted from December 2015 to April 2016. The field survey of the parasite was conducted from those patients attending the laboratories of the Alawi Children's Hospital in Rusafa and the Al-Yarmouk Teaching Hospital in Karkh, through which 1250 stool samples of different age groups were examined. Five groups of mice were used in the study; the first was injected with normal saline and considered as a negative control group, the second was injected with cystic form of non-irradiated Giardia lamblia and considered as a positive control group, whereas the other three groups were injected with gamma irradiated Giardia lamblia at three different doses 10, 15 and 25 rad respectively. Giardia lamblia was primarily cultivated in liver infusion agar for ten days to obtain the active phase. On the sixth day, the cystic phase was purified and standardized to be used in the infection of mice with or without the exposure of gamma rays. Mice showed high sensitivity to parasitic infestation, in the gamma non-irradiated and the irradiated with gamma 10 rad, and 15 rad irradiated groups which was 100%. The results expressed an excystation process of the depleted phases and the release of the feeder phases. The results of the three irradiated groups consisted of histopathological changes of the small, and the rectum by dissection after two weeks of infection, with intestine amputation lesions, as well as ulceration and inflammation of the inflammatory cells represented in small numbers of neutrophil, lymphocytes, and eosinophils. The presence of ulceration and fall of epithelial cells in the intestinal cavity has been shown, and different forms of the parasite have been observed. Mice which was injected with irradiated G lamblia at high dose (25 rad), not show and sensitivity to the challenge infection and no excystation of thy parasite had been done. After 2 wreaks, a comparison was achieved between all study groups in which no histopathological changes were noticed in the mice irradiated with dose of25 rad. After another two weeks, a challenge dose was given (un-attenuated G lamblia) and mice were dissected after another two weeks, no changes on the level of histopathology of intestinal tissue were noticed the results suggested that mice acquire an immunity against the parasite infection.

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