In vivo assessment of black seed oil single dose on prednisolone pharmacokinetics.

OBJECTIVES: To investigate the effect of blackseed oil (BSO) single dose on prednisolone pharmacokinetics via p-gp inhibition. METHODS: Three groups of rats (n = 5) were orally administered the vehicle, verapamil (50 mg/kg) or BSO (5 ml/kg) 15 min prior to prednisolone (5 mg/kg) administration. Blood samples were collected over 24 h and quantified. Non-compartmental analysis was employed to calculate maximum plasma concentration (Cmax), area under the curve (AUC0-last), time to reach Cmax (Tmax), apparent clearance (CL/F), and half-life (t1/2). Statistical significance was considered at p<0.05. RESULTS: Prednisolone Cmax and AUC0-last decreased by 65% and 25% in the BSO group compared to the negative control (P < .0001, .0029, respectively) while they increased by 1.75-folds and 8-folds in verapamil group (P < .0001). Tmax was achieved at 0.16, 0.5, and 0.25 h in the negative control, verapamil, and BSO-treated groups, respectively. CL/F in the treatment group was 1.3-fold and 10-fold higher compared to the negative and positive control, respectively, whereas the t1/2 remained comparable. CONCLUSION: Administration of BSO decreased prednisolone Cmax and AUC0-last in rats indicating that there is a herb-drug interaction; however, p-gp inhibition cannot be concluded. Patients relying on folk medicine in chronic illnesses treatment might need to avoid combining BSO with prednisolone.

The combined treatment of gold nanoparticles associated with photobiomodulation accelerate the healing of dermonecrotic lesion.

Introduction: The search for fast and efficient treatment for dermonecrotic lesions caused by the venom of the spider from the Loxosceles simillis, is a demand in health. Prednisolone is one of the most used drugs, however it has side effects. In this context, addictionally gold nanoparticles (GNPs) have anti-inflammatory, antioxidant, and antibacterial properties. The use of photobiomodulation has show to be efficient in the process of tissue repair. Therefore, the purpose of this study was to investigate the anti-inflammatory effect of photobiomodulation and GNPs associated or not with a low concentration of prednisolone in animal models of dermonecrotic lesion.Methodology: For this, rabbits with venon-induced dermonecrotic lesion were subjected to topical treatment with prednisolone + laser or GNPs + laser or Pred-GNPs + laser. The area of edema, necrosis and erythema were measured. On the last day of treatment, the animals were euthanized to remove the organs for histopathological and biochemical analysis.Results: All treatments combinations were effective in promoting the reduction of necrotic tissue and erythema.Conclusion: With this results, we suggest that the use of laser and nanoparticles, associated or not with prednisolone, should be considered for the treatment of dermonecrotic injury.

[State-of-the-art paradigm of corticosteroid therapy for immune-mediated inflammatory kidney diseases].

Since 1950's corticosteroids (CS) have remained the cornerstone of immunosuppressive therapy for immune-mediated kidney diseases. However multiple adverse events, associated with the prolonged CS therapy, became the basis for the development of novel treatment approaches. Current evidence supports the implementation of the steroid-sparing regimens for the treatment of different types of glomerulonephritis. Randomised controlled trial PEXIVAS demonstrated the efficacy and safety of early steroid tapering, starting from the second week of therapy, in patients with ANCA-associated vasculitis with kidney involvement. Several trials showed the efficacy of oral prednisolone 0.3-0.5 mg/kg/daily as a part of multitarget therapy for severe proliferative lupus nephritis. A combination of calcineurin inhibitors and low-dose CS are effective for remission induction in membranous nephropathy, as well as the steroid-free rituximab regimen for the patients with moderate risk of disease progression. Medium dose CS showed promising effect in patients with IgA-nephropathy. Long-term high dose CS remain the standard-of-care for the treatment of minimal change disease and focal segmental glomerulosclerosis, however patients with steroid-dependent and relapsing disease tacrolimus and rituximab can help to achieve steroid-sparing effect. The role of CS pulse-therapy is currently debated, nevertheless it remains a compulsory treatment in several conditions. Thus, overall trend is directed towards the minimization of the maximal doses of CS and/or treatment duration. However, to implement this approach morphological verification of the diagnosis and personalized assessment of the potential risk and benefit are required.

Immunomodulatory Effects of Combined Nicotinic Acid and Prednisolone in Adjuvant-induced Arthritis.

BACKGROUND: The combination of two drugs may lead to better results while reducing the need for each medication. OBJECTIVE: This study aimed to explore the synergistic benefits of combination therapy by suboptimal dose of niacin (Nic.) and prednisolone (Pred.) in an experimental model of Rheumatoid arthritis (RA). METHODS: About 50 male Wistar rats (weighing 150 - 160 grams) were randomly divided into five groups of ten, including healthy and RA groups treated with Nic. (80 mg/kg-orally), or Pred. (2 mg/kg-orally), and/or co-administration of Nic. and Pred. (half doses with each one-orally). RA was induced by the injection of complete Freund's adjuvant into the hind paw of each rat. All treatments were initiated on the fifth day following the induction and continued until day 30 post-induction. RESULTS: The combined Nic. and Pred. at half doses promoted a significant regression in the severity of the established RA, which is more pronounced than full doses of either drug alone. Combination therapy promoted a reduction in some hematological and biochemical RA parameters, like neutral red uptake by phagocytic cells, myeloperoxidase, nitric oxide, and C-reactive protein, more profound than each drug alone. Combined treatment caused a greater decrease in IFN-γ expression than other treatments in the area of plantar joints. All treatments were effective in increasing the expression of the IL-10 in the area of plantar joints. Prednisolone was less effective in reducing the expression of the TNF-α in the area of plantar joints than the other group. CONCLUSION: This combination may be a useful approach to controlling RA.

Clinical standards for the diagnosis and management of asthma in low- and middle-income countries.

BACKGROUND: The aim of these clinical standards is to aid the diagnosis and management of asthma in low-resource settings in low- and middle-income countries (LMICs).METHODS: A panel of 52 experts in the field of asthma in LMICs participated in a two-stage Delphi process to establish and reach a consensus on the clinical standards.RESULTS: Eighteen clinical standards were defined: Standard 1, Every individual with symptoms and signs compatible with asthma should undergo a clinical assessment; Standard 2, In individuals (>6 years) with a clinical assessment supportive of a diagnosis of asthma, a hand-held spirometry measurement should be used to confirm variable expiratory airflow limitation by demonstrating an acute response to a bronchodilator; Standard 3, Pre- and post-bronchodilator spirometry should be performed in individuals (>6 years) to support diagnosis before treatment is commenced if there is diagnostic uncertainty; Standard 4, Individuals with an acute exacerbation of asthma and clinical signs of hypoxaemia or increased work of breathing should be given supplementary oxygen to maintain saturation at 94-98%; Standard 5, Inhaled short-acting beta-2 agonists (SABAs) should be used as an emergency reliever in individuals with asthma via an appropriate spacer device for metered-dose inhalers; Standard 6, Short-course oral corticosteroids should be administered in appropriate doses to individuals having moderate to severe acute asthma exacerbations (minimum 3-5 days); Standard 7, Individuals having a severe asthma exacerbation should receive emergency care, including oxygen therapy, systemic corticosteroids, inhaled bronchodilators (e.g., salbutamol with or without ipratropium bromide) and a single dose of intravenous magnesium sulphate should be considered; Standard 8, All individuals with asthma should receive education about asthma and a personalised action plan; Standard 9, Inhaled medications (excluding dry-powder devices) should be administered via an appropriate spacer device in both adults and children. Children aged 0-3 years will require the spacer to be coupled to a face mask; Standard 10, Children aged <5 years with asthma should receive a SABA as-needed at step 1 and an inhaled corticosteroid (ICS) to cover periods of wheezing due to respiratory viral infections, and SABA as-needed and daily ICS from step 2 upwards; Standard 11, Children aged 6-11 years with asthma should receive an ICS taken whenever an inhaled SABA is used; Standard 12, All adolescents aged 12-18 years and adults with asthma should receive a combination inhaler (ICS and rapid onset of action long-acting beta-agonist [LABA] such as budesonide-formoterol), where available, to be used either as-needed (for mild asthma) or as both maintenance and reliever therapy, for moderate to severe asthma; Standard 13, Inhaled SABA alone for the management of patients aged >12 years is not recommended as it is associated with increased risk of morbidity and mortality. It should only be used where there is no access to ICS.The following standards (14-18) are for settings where there is no access to inhaled medicines. Standard 14, Patients without access to corticosteroids should be provided with a single short course of emergency oral prednisolone; Standard 15, Oral SABA for symptomatic relief should be used only if no inhaled SABA is available. Adjust to the individual's lowest beneficial dose to minimise adverse effects; Standard 16, Oral leukotriene receptor antagonists (LTRA) can be used as a preventive medication and is preferable to the use of long-term oral systemic corticosteroids; Standard 17, In exceptional circumstances, when there is a high risk of mortality from exacerbations, low-dose oral prednisolone daily or on alternate days may be considered on a case-by-case basis; Standard 18. Oral theophylline should be restricted for use in situations where it is the only bronchodilator treatment option available.CONCLUSION: These first consensus-based clinical standards for asthma management in LMICs are intended to help clinicians provide the most effective care for people in resource-limited settings.

Glucocorticoid supplementation during ovulation induction for assisted reproductive technology: a systematic review and meta-analysis.

BACKGROUND: There is ongoing interest in glucocorticoid treatment during oocyte stimulation to treat infertility in women who have undergone Assisted Reproductive Technology (ART). OBJECTIVE: This meta-analysis was performed to evaluate the efficiency and safety of adjuvant glucocorticoid therapy on pregnancy outcomes in infertile women undergoing ART cycles. STUDY DESIGN: A literature search was performed in PubMed, EMBASE, Web of Science, and the Cochrane Library up to December 2022. To assess the efficacy and safety of additional glucocorticoid treatment during ovulation induction in women who underwent IVF or ICSI treatment, only randomized controlled trials were included. RESULTS: Overall, glucocorticoid therapy during ovulation showed a nonsignificant effect of prednisolone improving the live birth rate (OR = 1.03, 95% CI [.75, 1.43], I2 = .0%, p = .84), abortion rate (OR = 1.14, 95% CI [.62, 2.08], I2 = 31%, p = .68), and implantation rate (OR = 1.1, 95% CI [.82, 1.5], I2 = 8%, p = .52) of infertile women compared to the control group. The present meta-analysis revealed that the clinical pregnancy rate per cycle tended to increase after glucocorticoid treatment (OR = 1.29, 95% CI [1.02, 1.63], I2 = 8%, p = .52). CONCLUSIONS: The present meta-analysis suggested that ovarian stimulation prednisolone therapy does not significantly improve clinical outcomes in women undergoing IVF/ICSI. Although the results indicated that adjuvant glucocorticoid therapy during ovarian stimulation may increase the clinical pregnancy rate, subgroup analysis showed that it was affected by infertility factors, dose schedules, and length of treatment. Therefore, these results should be interpreted with caution.

Changes in bone turnover markers after discontinuing long-term glucocorticoid administration in children with idiopathic nephrotic syndrome: a multicenter retrospective observational study.

BACKGROUND: Glucocorticoids affect bone turnover. Little is known about how bone turnover changes when glucocorticoids are discontinued following long-term administration. METHODS: This retrospective observational study was conducted on the relationship between discontinuation of long-term administration of glucocorticoid and bone turnover markers (BTMs) in patients with childhood-onset idiopathic nephrotic syndrome. Serum bone alkaline phosphatase (BAP), intact procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase-5b (TRACP-5b) were evaluated as BTMs. RESULTS: Thirty-eight pairs of BTMs at glucocorticoid administration and after discontinuation were analyzed in 29 patients. The median age at baseline was 12.4 (interquartile range, 9.0-14.5) years, and the median time from the onset of nephrotic syndrome was 5.9 (3.3-9.7) years. The mean period from prednisolone discontinuation to the measurement of BTMs after glucocorticoid discontinuation was 3.5 ± 1.0 months. Changes in BTMs after glucocorticoid discontinuation were modest when the daily prednisolone dose was < 0.25 mg/kg/day (ln BAP standard deviation [SD] score, p = 0.19; log intact P1NP SD score, p = 0.70; TRACP-5b, p = 0.95). When the daily prednisolone dose was ≥ 0.25 mg/kg/day, all BTMs increased significantly after glucocorticoid discontinuation (ln BAP SD score, p < 0.01; log intact P1NP SD score, p < 0.01; TRACP-5b, p < 0.01). CONCLUSIONS: Decreased BTMs can rise within a few months of discontinuing long-term glucocorticoid administration. When the administered glucocorticoid dose is low, changes in BTMs may be small. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical features and long-term management of cats with primary hypoadrenocorticism using desoxycorticosterone pivalate and prednisolone.

BACKGROUND: Primary hypoadrenocorticism (PH) is rare in cats and knowledge about treatment is sparse. OBJECTIVE: To describe cats with PH with a focus on long-term treatment. ANIMALS: Eleven cats with naturally occurring PH. METHODS: Descriptive case series with data on signalment, clinicopathological findings, adrenal width, and doses of desoxycorticosterone pivalate (DOCP) and prednisolone during a follow-up period of >12 months. RESULTS: Cats ranged from 2 to 10 years (median 6.5); 6 cats were British Shorthair. Most common signs were reduced general condition and lethargy, anorexia, dehydration, obstipation, weakness, weight loss, and hypothermia. Adrenal glands on ultrasonography were judged small in 6. Eight cats could be followed for 14 to 70 months (median: 28). Two were started on DOCP doses ≥2.2 mg/kg (2.2; 2.5) and 6 < 2.2 mg/kg (1.5-2.0 mg/kg, median 1.8) q28 days. Both high-dose cats and 4 low-dose cats needed a dose increase. Desoxycorticosterone pivalate and prednisolone doses at the end of the follow-up period were 1.3 to 3.0 mg/kg (median: 2.3) and 0.08 to 0.5 mg/kg/day (median: 0.3), respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Desoxycorticosterone pivalate and prednisolone requirements in cats were higher than what is currently used in dogs; thus, a DOCP starting dose of 2.2 mg/kg q28 days and a prednisolone maintenance dose of 0.3 mg/kg/day titrated to the individual need seems warranted. Small adrenal glands (width < 2.7 mm) on ultrasonography in a cat suspected of hypoadrenocorticism can be suggestive of the disease. The apparent predilection of British Shorthaired cats for PH should be further evaluated.

[A Case of Unilateral Interstitial Lung Disease in a Patient Treated with Oxaliplatin, 5-Fluorouracil, and Leucovorin].

Respiratory symptoms are rarely reported as side effects of oxaliplatin, 5-fluorouracil, and Leucovorin(FOLFOX)therapy. We report a case of a patient with FOLFOX-induced unilateral interstitial pneumonia. The patient was a 68-year-old man who underwent ileocecal resection of cecum cancer. FOLFOX regimen was started as an adjuvant chemotherapy. After the administration of 11 courses, he visited our hospital with fever, dyspnea, and anorexia. We diagnosed this as FOLFOX- induced unilateral interstitial pneumonia through a blood test, chest radiograph, computed tomography, and bronchoscopy. Treatment was started with 30 mg of prednisolone, and the dosage was gradually decreased. The patient responded well to the treatment and was discharged from the hospital without any complications on the 33th day after admission.

Oleander-Associated Keratitis and Uveitis.

PURPOSE: Oleander is a poisonous plant with extensively documented systemic side effects; however, oleander's ophthalmic side effects have not been detailed in the literature. We report a case of oleander-associated keratitis with subsequent corneal edema and anterior uveitis. METHODS: This is a case report and review of relevant literature. RESULTS: A 58-year-old woman presented with large corneal epithelial defect after being struck in the eye with an oleander leaf. Despite treatment with topical moxifloxacin, she developed severe corneal edema and anterior uveitis. A diagnosis of oleander-associated ocular inflammation with secondary corneal edema was made, given the temporal relationship, and treatment was initiated with topical prednisolone and cyclopentolate. However, the corneal edema and inflammation continued to progress until oral prednisone and topical difluprednate were initiated. Visual acuity, anterior uveitis, and corneal edema significantly improved with aggressive immunomodulation. Follow-up at 1 month confirmed complete recovery of symptoms, corneal edema and anterior uveitis. CONCLUSIONS: Severe corneal edema and anterior uveitis can be associated with oleander exposure. Aggressive treatment with oral and topical steroids may be required without persistent sequelae at the 5-month follow-up. Ophthalmologists should consider this inflammatory reaction if patients experience ocular exposure to oleander.

Targeted AntiBiotics for Chronic pulmonary diseases (TARGET ABC): can targeted antibiotic therapy improve the prognosis of Pseudomonas aeruginosa-infected patients with chronic pulmonary obstructive disease, non-cystic fibrosis bronchiectasis, and asthma? A multicenter, randomized, controlled, open-label trial.

BACKGROUND: Pseudomonas aeruginosa infection is seen in chronic pulmonary disease and is associated with exacerbations and poor long-term prognosis. However, evidence-based guidelines for the management and treatment of P. aeruginosa infection in chronic, non-cystic fibrosis (CF) pulmonary disease are lacking. The aim of this study is to investigate whether targeted antibiotic treatment against P. aeruginosa can reduce exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis, and asthma. METHODS: This study is an ongoing multicenter, randomized, controlled, open-label trial. A total of 150 patients with COPD, non-CF bronchiectasis or asthma, and P. aeruginosa-positive lower respiratory tract samples will be randomly assigned with a 1:1 ratio to either no antibiotic treatment or anti-pseudomonal antibiotic treatment with intravenous beta-lactam and oral ciprofloxacin for 14 days. The primary outcome, analyzed with two co-primary endpoints, is (i) time to prednisolone and/or antibiotic requiring exacerbation or death, in the primary or secondary health sector, within days 20-365 from study allocation and (ii) days alive and without exacerbation within days 20-365 from the study allocation. DISCUSSION: This trial will determine whether targeted antibiotics can benefit future patients with chronic, non-CF pulmonary disease and P. aeruginosa infection in terms of reduced morbidity and mortality, thus optimizing therapeutic approaches in this large group of chronic patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03262142 . Registered on August 25, 2017.

The anti-inflammatory effect of myrrh ethanolic extract in comparison with prednisolone on an autoimmune disease rat model induced by silicate.

Autoimmune disease is a complex chronic disease that triggers immune activation against autoantigens resulting in tissue damage. Epidemiological data showed that autoimmune diseases are increasing worldwide over the last decades owing to increased environmental pollution. This study investigates the therapeutic effect of myrrh as a natural medicine compared to prednisolone in the treatment of immune-mediated glomerulonephritis induced by silicate. The autoimmune disease model in rats was induced by injecting 5 mg crystalline sodium silicate suspension subcutaneously once weekly for 20 weeks, and then the rats were treated either with myrrh extract or prednisolone or with both for 6 weeks. Liver and kidney function tests, histopathology, and immunohistochemistry of TNF-α expression in kidney tissue were performed. The creatinine significantly elevated in silica-treated group and decreased in other treated groups. Histopathology of the kidney revealed improvement of glomerular and tubular basement thickness in all treated groups, but the inflammatory cell count slightly decreased in the group treated with myrrh than the other treated groups which showed a marked decrease. TNF-α expression was significantly decreased in all treated groups. Interestingly, the myrrh did not produce hepatic lesions and improve the side effect of prednisolone in the liver when taken in combination. Therefore, myrrh extract possessed anti-inflammatory properties and counteracted the side effect of prednisolone on the liver. Myrrh extract can serve as a conjunctive therapy with prednisolone to treat autoimmune diseases.

The Swedish national guidelines on prostate cancer, part 1: early detection, diagnostics, staging, patient support and primary management of non-metastatic disease.

OBJECTIVE: There is now an unprecedented amount of evidence to consider when revising prostate cancer guidelines. We believe that there is a value in publishing summaries of national clinical guidelines in English for others to read and comment on. METHODS: This is part 1 of a summary of the Swedish prostate cancer guidelines that were published in June 2022. It covers the early detection, diagnostics, staging, patient support and management of the non-metastatic disease. Part 2 covers recurrence after local treatment and management of the metastatic disease. RESULTS: The 2022 Swedish guidelines include several new recommendations: rectal iodine-povidone to reduce post-biopsy infections, external beam radiation with focal boost to the tumour, use of a pre-rectal spacer to reduce rectal side effects after external beam radiotherapy in some expert centres, 6 months' concomitant and adjuvant rather than neoadjuvant and concomitant hormonal treatment together with radiotherapy for unfavourable intermediate and high-risk disease, and adjuvant abiraterone plus prednisolone together with a GnRH agonist for a subgroup of men with very high-risk disease. The Swedish guidelines differ from the European by having more restrictive recommendations regarding genetic testing and pelvic lymph node dissection, the risk group classification, recommending ultra-hypofractionated (7 fractions) external radiotherapy for intermediate and selected high-risk cancers, by not recommending any hormonal treatment together with radiotherapy for favourable intermediate-risk disease, and by recommending bicalutamide monotherapy instead of a GnRH agonist for some patient groups. CONCLUSIONS: The 2022 Swedish prostate cancer guidelines include several new recommendations and some that differ from the European guidelines.

Trivalent chromium supplementation ameliorates adjuvant induced rheumatoid arthritis through up-regulation of FOXP3 and decrease in synovial Cathepsin G expression.

BACKGROUND: Rheumatoid arthritis (RA) is a known debilitating autoimmune disease. Immune-suppressants that are used for disease treatment have serious side effects, therefore, trivalent chromium (Cr (III)); which has shown evidence of its influences on some inflammatory pathways and cytokines; was used in this study for the first time to be assessed for its therapeutic effect in RA rat model and was compared to prednisolone in a trial to find a treatment with lesser side effects. METHODS: Adult male albino rats were randomly divided into four groups: normal, untreated RA, prednisolone treated RA (1.25 mg/kg/day) and Cr (III) treated RA groups (80 µg/kg/day), induction of RA was done by subcutaneous complete Freund adjuvant injection. Study duration was 4 weeks throughout which arthritis scoring and weight measurement were pursued. Histopathological examination and immunohistochemical FOXP3 assessment were done for joint biopsies. Serum inflammatory markers (interleukin 17, interleukin 10, CRP) and synovial erosive arthritis marker (Cathepsin G) were measured. HDL and non-HDL cholesterol were estimated as well. RESULTS: Cr (III) treatment showed marked clinical and histopathological improvement, also astonishing anti-inflammatory effects (increase in FOXP3 expression and interleukin 10, with decrease in interleukin 17, CRP and synovial Cathepsin G) to the extent that Cr (III) effects on inflammation abolishment were comparable to that of prednisolone and even better at some aspects. Moreover, Cr (III) was protective from side effects, i.e., weight gain and dyslipidemia that were seen with prednisolone treatment. CONCLUSIONS: Cr (III) is promising in treating RA and it lacks some side effects of accustomed immune-modulatory agents including prednisolone. Further experimental studies and clinical trials should be held to see the efficacy of Cr (III) in different doses and to assess its long term side effects when used for rheumatoid arthritis and other autoimmune diseases treatment.

Bilateral Vitreous Hemorrhage in a Young Man with Pustular Psoriasis.

A 25-year-old man consulted us with a severe exacerbation of pustular psoriasis for 10 days (Figure 1). The patient had pustular psoriasis for the last 12 years. During his hospital stay, he suffered sudden painless and profound loss of vision in both eyes. Subsequently, he was referred to an ophthalmologist. Slit lamp examination of both eyes revealed the presence of a clot in anterior chamber with neovascularization of the iris and the fibrovascular membrane covering the pupil and iris bombe formation nasally and inferiorly (Figure 2a). B-scan ultrasonography showed bilateral vitreous hemorrhage with normal optic nerve head in the right eye and an optic nerve cyst in the left eye (Figure 3). His erythrocyte sedimentation rate was 32.0 mm/hour, while blood and urine screening tests along with review of other systems were found to be normal. The fundi were not visualized due to dense hemorrhage. There was no history of trauma, recent ocular surgery, diabetes, hypertension, hematologic abnormalities, and drug intake known to cause vitreous hemorrhage. Topical medication (eye drop atropine 1%, timolol 0.5%, moxifloxacin and dexamethasone combination) and oral prednisolone (60 mg per day for 2 weeks) were prescribed but were later withdrawn in view of no response and worsening of skin condition. In the past, he had received various treatments, including phototherapy, acitretin, methotrexate, apremilast, cyclosporine, and mycophenolate mofetil; however, his condition was recalcitrant.

Anti-inflammatory response of cardamom extract and prediction of therapeutic window in COVID-19 patients by assessing inflammatory markers using RT-PCR.

INTRODUCTION: Molecular diagnostics using RT-PCR has now emerged as the new diagnostic method for clinicians with the dawn of SARS-CoV-2. In India, the popularity and awareness of RT-PCR and particularly the increased availability of testing machines across hospitals has now opened up possibilities of diagnostic tests with RT-PCR. In view of the cytokine storm which is the significant reason for morbidity and mortality of COVID-19 patients, we proposed to test the usefulness of a multiplex RT-PCR test kit that simultaneously measured inflammatory markers namely, IL-6, TNF- α and IL-10 (IFM) all in one tube. The study included a group of patients who were equally allotted to two treatment arms one of which received standard of care along with a food supplement capsule as a natural anti-inflammatory (RECOVEREEZ FORTE™), and the other group received standard of care that included oral Prednisolone tablets in tapered dosage. RECOVEREEZ FORTE™ consists of potent biomolecules from cardamom extract. A natural product with substantial anti-inflammatory action when consumed early at the onset of symptoms is hereby proven by comparing gene expression profile of inflammatory markers with routinely tested inflammatory parameters such as serum IL-6, CRP and LDH. In addition to predicting worse disease outcomes beforehand, RT-PCR assay tests provides an opportunity for identifying therapeutic window aiding in practicing effective treatment strategy for COVID-19. RT-PCR analysis of IFM together being used in a single multiplex kit is being first reported and such a test as a prognosticator for disease progression does seem promising and worthy of clinicians adopting novel testing modalities in clinical practice. AIM OF THE STUDY: To study the anti-inflammatory response of RECOVEREEZ FORTE™ using RT-PCR based multiplex gene profiling of inflammatory markers in disease prognosis and show its predictability of worsening outcomes and its role in identifying therapeutic window for RECOVEREEZ FORTE™. To show the potentiality of RECOVEREEZ FORTE™ in reducing COVID-19 symptoms and SARS-CoV-2 RT-PCR Ct values of the treatment group. MATERIALS AND METHODS: This was a short study of a 10-day period where the end point was the negativity of COVID-19 on RT-PCR test or the decline in cycle threshold (Ct) values of the test performed on day 10 when compared to day 0. During the course of the study, patients were given standard treatment and an oral dose of 500 mg of RECOVEREEZ FORTE™ thrice daily, or standard of care and oral Prednisolone in tapered dosage (control group). All essential interventions were included in the standard of care as decided by the attending physician. The RT-PCR results of inflammatory markers were compared to routinely tested parameters such as IL-6, CRP and LDH. Time to clinical improvement was in terms of SARS-CoV-2 RT-PCR test negativity or recovery of COVID-19 symptoms. We enrolled 64 patients, of which 32 were allocated to RECOVEREEZ FORTE ™ group and 32 to the control group. RESULTS: The RT-PCR analysis of elevated IFM on day 0 corresponded to above normal protein levels of routinely tested parameters such as serum IL-6, CRP and LDH on day 5. Similarly, elevated IFM on day 5 corresponded to above normal protein levels on day 10. Such an association was equally prevalent in both the control group and RECOVEREEZ FORTE™ group, stipulating that RECOVEREEZ FORTE™ may be used as an alternative to steroids. The obtained results indicate that the RT-PCR assessment predicts worse outcomes 5 days earlier. But, the RT-PCR analysis of elevated IFM on day 0 did not correspond to the above normal protein levels of other parameters on day 10. Hence, indicating that the IFM RT-PCR test cannot predict worse outcomes 10 days earlier. Also, RECOVEREEZ FORTE™ when consumed for a period of 10 days normalized LDH values, compared to the control group. Moreover, IFM RT-PCR test identified a 5-day therapeutic window for RECOVEREEZ FORTE™ against inflammation experienced by patients. In addition to the above findings, the authors also observed that majority of the patients belonging to the treatment group showed recovery from symptoms such as fever, cough, sore throat and breathlessness compared to control group by day 5. 12 (37.5%) out of 32 patients and 6 (18.75%) out of 32 patients belonging to the treatment group and control group, respectively, became SARS-CoV-2 negative by day 5, indicating a probable anti-viral action of RECOVEREEZ FORTE™ against SARS-CoV-2. CONCLUSION: The IFM RT-PCR test possess 5-day early prediction ability and lacks 10-day prediction ability. Treatment with RECOVEREEZ FORTE™ indicates good anti-inflammatory action which is equivalent to steroids. Intake of RECOVEREEZ FORTE ™ for a period of 5 days depicts persistent anti-inflammatory action, recovery of COVID-19 symptoms and a probable anti-viral action. Moreover, an effective normalization of LDH may be rendered by RECOVEREEZ FORTE™ when consumed for a period of 10 days.

Paeonia lactiflora extract improves the muscle function of mdx mice, an animal model of Duchenne muscular dystrophy, via downregulating the high mobility group box 1 protein.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeonia lactiflora Pall. is an ethnopharmacological medicine with a long history of human use for treating various inflammatory diseases in many Asian countries. AIM OF THE STUDY: Duchenne muscular dystrophy (DMD) is an X-linked degenerative muscle disease affecting 1 in 3500 males and is characterized by severe muscle inflammation and a progressive decline in muscle function. This study aimed to elucidate the effects of an ethanol extract of the root of Paeonia lactiflora Pall. (PL) on the muscle function in the muscular dystrophy X-linked (mdx) mouse, the most commonly used animal model of DMD. MATERIALS AND METHODS: Male mdx mice and wild-type controls aged 5 weeks were orally treated with PL for 4 weeks. The corticosteroid prednisolone was used as a comparator drug. Muscle strength and motor coordination were assessed via the grip-strength and rotarod tests, respectively. Muscle damage was evaluated via histological examination and assessment of plasma creatine-kinase activity. Proteomic analyses were conducted to identify the muscle proteins whose levels were significantly affected by PL (ProteomeXchange identifier: PXD028886). Muscle and plasma levels of these proteins, and their corresponding mRNAs were measured using western blotting and ELISA, and quantitative reverse transcription-polymerase chain reaction, respectively. RESULTS: The muscle strength and motor coordination of mdx mice were significantly increased by the oral treatment of PL. PL significantly reduced the histological muscle damage and plasma creatine-kinase activity. Proteomic analyses of the muscle showed that PL significantly downregulated the high mobility group box 1 (HMGB1) protein and Toll-like receptor (TLR) 4, thus suppressing the HMGB1-TLR4-NF-κB signaling, in the muscle of mdx mice. Consequently, the muscle levels of proinflammatory cytokines/chemokines, which play crucial roles in inflammation, were downregulated. CONCLUSION: PL improves the muscle function and reduces the muscle damage in mdx mice via suppressing the HMGB1-TLR4-NF-κB signaling and downregulating proinflammatory cytokines/chemokines.

Combining explainable machine learning, demographic and multi-omic data to inform precision medicine strategies for inflammatory bowel disease.

Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, affect several million individuals worldwide. These diseases are heterogeneous at the clinical, immunological and genetic levels and result from complex host and environmental interactions. Investigating drug efficacy for IBD can improve our understanding of why treatment response can vary between patients. We propose an explainable machine learning (ML) approach that combines bioinformatics and domain insight, to integrate multi-modal data and predict inter-patient variation in drug response. Using explanation of our models, we interpret the ML models' predictions to infer unique combinations of important features associated with pharmacological responses obtained during preclinical testing of drug candidates in ex vivo patient-derived fresh tissues. Our inferred multi-modal features that are predictive of drug efficacy include multi-omic data (genomic and transcriptomic), demographic, medicinal and pharmacological data. Our aim is to understand variation in patient responses before a drug candidate moves forward to clinical trials. As a pharmacological measure of drug efficacy, we measured the reduction in the release of the inflammatory cytokine TNFα from the fresh IBD tissues in the presence/absence of test drugs. We initially explored the effects of a mitogen-activated protein kinase (MAPK) inhibitor; however, we later showed our approach can be applied to other targets, test drugs or mechanisms of interest. Our best model predicted TNFα levels from demographic, medicinal and genomic features with an error of only 4.98% on unseen patients. We incorporated transcriptomic data to validate insights from genomic features. Our results showed variations in drug effectiveness (measured by ex vivo assays) between patients that differed in gender, age or condition and linked new genetic polymorphisms to patient response variation to the anti-inflammatory treatment BIRB796 (Doramapimod). Our approach models IBD drug response while also identifying its most predictive features as part of a transparent ML precision medicine strategy.

Successful treatment of ascites accumulation and diarrhea associated with protein-losing enteropathy with oral equine placenta extract supplementation in a dog: A case report.

Background: Protein-losing enteropathy (PLE) is characterized by leakage of serum proteins into the intestinal lumen, indicating hypoproteinemia. Immunosuppressive agents are the mainstay of treatment, but in many cases, patients are forced to taper off early owing to the induction of liver damage. Case Description: An 8-year-old, non-spayed female Chihuahua presented with diarrhea and ascites effusion lasting 2 weeks. Based on the results of radiography and blood tests, a diagnosis of PLE was made. Prednisolone (3 mg/kg semel in die [SID]) and MitoMax (200 mg/day) were administered, but ascites accumulation and diarrhea did not improve. Thus, azathioprine (2 mg/kg/day) was added, but there was no improvement, and liver damage developed. The liver injury did not improve immediately, but diarrhea and ascites effusion improved after serum total protein and serum albumin levels increased after they had decreased. Subsequent tapering of prednisolone from 3 mg/kg SID to 1 mg/kg SID, combined with MitoMax (200 mg/day) and equine placenta extract (eqPE) (2 ml/day), resulted in no recurrence of ascites or diarrhea. Conclusion: In canine PLE with prolonged diarrhea and ascites effusion, supplementation with eqPE may be considered a reasonable additional therapeutic strategy.

An innovative targeted therapy for fluoroscopy-induced chronic radiation dermatitis.

Fluoroscopy-induced chronic radiation dermatitis (FICRD) is a complication of fluoroscopy-guided intervention. Unlike acute radiation dermatitis, FICRD is different as delayed onset and usually appears without preexisting acute dermatitis. Unfortunately, the chronic and progressive pathology of FICRD makes it difficult to treat, and some patients need to receive wide excision and reconstruction surgery. Due to lack of standard treatment, investigating underlying mechanism is needed in order to develop an effective therapy. Herein, the Hippo pathway is specifically identified using an RNA-seq analysis in mild damaged skin specimens of patients with FICRD. Furthermore, specific increase of the Yes-associated protein (YAP1), an effector of the Hippo pathway, in skin region with mild damage plays a protective role for keratinocytes via positively regulating the numerous downstream genes involved in different biological processes. Interestingly, irradiated-keratinocytes inhibit activation of fibroblasts under TGF-ß1 treatment via remote control by an exosome containing YAP1. More importantly, targeting one of YAP1 downstream genes, nuclear receptor subfamily 3 group C member 1 (NR3C1), which encodes glucocorticoid receptor, has revealed its therapeutic potential to treat FICRD by inhibiting fibroblasts activation in vitro and preventing formation of radiation ulcers in a mouse model and in patients with FICRD. Taken together, this translational research demonstrates the critical role of YAP1 in FICRD and identification of a feasible, effective therapy for patients with FICRD. KEY MESSAGES: • YAP1 overexpression in skin specimens of radiation dermatitis from FICRD patient. • Radiation-induced YAP1 expression plays protective roles by promoting DNA damage repair and inhibiting fibrosis via remote control of exosomal YAP1. • YAP1 positively regulates NR3C1 which encodes glucocorticoid receptor expression. • Targeting glucocorticoid receptor by prednisolone has therapeutic potential for FICRD patient.