Codelivery of ivermectin and methyl dihydrojasmonate in nanostructured lipid carrier for synergistic antileukemia therapy.

Chronic myeloid leukemia is a life-threatening blood-cancer prevalent among children and adolescents. Research for innovative therapeutics combine drug-repurposing, phytotherapeutics and nanodrug-delivery. Ivermectin (Ivn) is a potent anthelmintic, repurposed for antileukemic-activity. However, Ivn exerts off-target toxicity. Methyl-dihydrojasmonate (MJ) is a phytochemical of known antileukemic potential. Herein, we developed for the first-time Ivn/MJ-coloaded nanostructured-lipid-carrier (Ivn@MJ-NLC) for leveraging the antileukemic-activity of the novel Ivn/MJ-combination while ameliorating possible adverse-effects. The developed Ivn@MJ-NLC possessed optimum-nanosize (97 ± 12.70 nm), PDI (0.33 ± 0.02), entrapment for Ivn (97.48 ± 1.48 %) and MJ (99.48 ± 0.57 %) and controlled-release of Ivn (83 % after 140 h) and MJ (80.98 ± 2.45 % after 48 h). In-vitro K562 studies verified Ivn@MJ-NLC prominent cytotoxicity (IC50 = 35.01 ± 2.23 µg/mL) with pronounced Ivn/MJ-synergism (combination-index = 0.59) at low-concentrations (5-10 µg/mL Ivn). Superior Ivn@MJ-NLC cytocompatibility was established on oral-epithelial-cells (OEC) with high OEC/K562 viability-ratio (1.49-1.85). The innovative Ivn@MJ-NLC enhanced K562-nuclear-fragmentation and afforded upregulation of caspase-3 and BAX (1.71 ± 0.07 and 1.45 ± 0.07-fold-increase, respectively) compared to control. Ex-vivo hemocompatibility and in-vivo-biocompatibility of parenteral-Ivn@MJ-NLC, compared to Ivn-solution, was verified via biochemical-blood analysis, histological and histomorphometric studies of liver and kidney tissues. Our findings highlight Ivn@MJ-NLC as an Ivn/MJ synergistic antileukemic platform, ameliorating possible adverse-effects.

Drug repurposing-based nanoplatform via modulating autophagy to enhance chemo-phototherapy against colorectal cancer.

Multi-modal combination therapy is regarded as a promising approach to cancer treatment. Combining chemotherapy and phototherapy is an essential multi-modal combination therapy endeavor. Ivermectin (IVM) is a potent antiparasitic agent identified as having potential antitumor properties. However, the fact that it induces protective autophagy while killing tumor cells poses a challenge to its further application. IR780 iodide (IR780) is a near-infrared (NIR) dye with outstanding photothermal therapy (PTT) and photodynamic therapy (PDT) effects. However, the hydrophobicity, instability, and low tumor uptake of IR780 limit its clinical applications. Here, we have structurally modified IR780 with hydroxychloroquine, an autophagy inhibitor, to synthesize a novel compound H780. H780 and IVM can form H780-IVM nanoparticles (H-I NPs) via self-assembly. Using hyaluronic acid (HA) to modify the H-I NPs, a novel nano-delivery system HA/H780-IVM nanoparticles (HA/H-I NPs) was synthesized for chemotherapy-phototherapy of colorectal cancer (CRC). Under NIR laser irradiation, HA/H-I NPs effectively overcame the limitations of IR780 and IVM and exhibited potent cytotoxicity. In vitro and in vivo experiment results showed that HA/H-I NPs exhibited excellent anti-CRC effects. Therefore, our study provides a novel strategy for CRC treatment that could enhance chemo-phototherapy by modulating autophagy.

Evaluation of the mosquitocidal efficacy of fluralaner, a potential candidate for drug based vector control.

Vector control is a key intervention against mosquito borne diseases. However, conventional methods have several limitations and alternate strategies are in urgent need. Vector control with endectocides such as ivermectin is emerging as a novel strategy. The short half-life of ivermectin is a limiting factor for its application as a mass therapy tool for vector control. Isoxazoline compounds like fluralaner, a class of veterinary acaricides with long half-life hold promise as an alternative. However, information about their mosquitocidal effect is limited. We explored the efficacy of fluralaner against laboratory reared vector mosquitoes-Aedes aegypti, Anopheles stephensi, and, Culex quinquefasciatus. 24 h post-blood feeding, fluralaner showed a significant mosquitocidal effect with LC50 values in the range of 24.04-49.82 ng/mL for the three different mosquito species tested. Effects on life history characteristics (fecundity, egg hatch success, etc.) were also observed and significant effects were noted at drug concentrations of 20, 25 and 45 ng/mL for Ae. aegypti, An. stephensi, and, Cx. quinquefasciatus respectively. At higher drug concentration of 250 ng/mL, significant mortality was observed within 1-2 h of post blood feeding. Potent mosquitocidal effect coupled with its long half-life makes fluralaner an excellent candidate for drug based vector control strategies.

Exploring the antifilarial potential of an important medicinal plant Typhonium trilobatum (L. Schoot): Isolation, characterization, and structural elucidation of bioactive compounds against Brugia malayi.

ETHNOPHARMACOLOGY RELEVANCE: The plant Typhonium trilobatum has been utilized in traditional medicine for the treatment of many ailments, including parasitic infections. Recent examinations indicate that the bioactive substances from this plant may have antiparasitic activities against Brugia malayi, which have not been determined. PURPOSE: The parasitic nematodes Brugia malayi, Brugia timori, and Wuchereria bancrofti causing lymphatic filariasis, remain a significant challenge to global public health. Given the ongoing nature of this enduring menace, the current research endeavours to examine the efficacy of an important medicinal plant, Typhonium trilobatum. METHODS: Different extracts of the T. trilobatum tubers were evaluated for their antiparasitic activity. The most prominent extract was subjected to Gas Chromatography Mass Spectrometry (GC-MS) and High Performance Liquid Chromatography (HPLC) followed by Column Chromatography for isolating bioactive molecules. The major compounds were isolated and characterized based on different spectroscopic techniques (FTIR, NMR and HRMS). Further, the antiparasitic activity of the isolated compounds was evaluated against B. malayi and compared with clinically used antifilarial drugs like Diethylcarbamazine and Ivermectin. RESULTS: The methanolic extract of the tuber exhibited significant antiparasitic activity compared to the other extracts. The bioactive molecules isolated from the crude extract were identified as Linoleic acid and Palmitic acid. Antiparasitic activity of both the compounds has been performed against B. malayi and compared with clinically used antifilarial drugs, Ivermectin and DEC. The IC50 value of Linoleic acid was found to be 6.09 ± 0.78 µg/ml after 24 h and 4.27 ± 0.63 µg/ml after 48 h, whereas for Palmitic acid the value was 12.35 ± 1.09 µg/ml after 24 h and 8.79 ± 0.94 µg/ml after 48 h. The IC50 values of both the molecules were found to be similar to the standard drug Ivermectin (IC50 value of 11.88 ± 1.07 µg/ml in 24 h and 2.74 ± 0.43 µg/ml in 48 h), and much better compared to the DEC (IC50 values of 194.2 ± 2.28 µg/ml in 24 h and 101.8 ± 2.06 µg/ml in 48 h). Furthermore, it has been observed that both the crude extracts and the isolated compounds do not exhibit any detrimental effects on the J774.A.1 macrophage cell line. CONCLUSION: The isolation and characterization of bioactive compounds present in the methanolic tuber extract of Typhonium trilobatum were explored. Moreover, the antimicrofilarial activity of the crude extracts and its two major compounds were determined using Brugia malayi microfilarial parasites without any significant side effects.

Citrus reticulata peel extract mitigates oxidative stress and liver injury induced by abamectin in rats.

The prevalent use of abamectin (ABM) has latterly raised safety attention as it has different toxicities to non-target living organisms. Citrus fruits are widely renowned for their nutritional and health-promoting qualities, and their peels are full of phenolic constituents. The purpose of the current study was to evaluate the modulatory effectiveness of Citrus reticulata peel extract (CPE) against abamectin-induced hepatotoxicity and oxidative injury. Rats were distributed into 4 groups as follows: control, CPE (400 mg/kg bw orally for 14 days), ABM (2 mg/kg bw for 5 days), and CPE + ABM at the doses mentioned above. Results revealed that GC-MS analysis of CPE has 19 identified components with significant total phenolic and flavonoid contents. Treatment with ABM in rats displayed significant variations in enzymatic and non-enzymatic antioxidants, oxidative stress markers (MDA, H2O2, PCC), liver and kidney function biomarkers, hematological parameters, lipids, and protein profile as well as histopathological abnormalities, inflammation and apoptosis (TNF-α, Caspase-3, NF-κB, and Bcl-2 genes) in rats' liver. Supplementation of CPE solo dramatically improved the antioxidant state and reduced oxidative stress. C. reticulata peel extract pretreatment alleviated ABM toxicity by modulating most of the tested parameters compared to the ABM group. Conclusively, CPE had potent antioxidant activity and could be used in the modulation of ABM hepatotoxicity presumably due to its antioxidant, anti-inflammatory, and gene-regulating capabilities.

Mortality of hospitalized patients with COVID-19: Effects of treatment options (vitamin D, anticoagulation, isoprinosine, ivermectin) assessed by propensity score matching, retrospective analysis.

INTRODUCTION: SARS-CoV-2 respiratory infection is associated with significant morbidity and mortality, especially in hospitalized high-risk patients. We aimed to evaluate the effects of treatment options (vitamin D, anticoagulation, isoprinosine, ivermectin) on hospital mortality in non-vaccinated patients during the 2021 spring wave in the Czech Republic. METHODS: Initially, 991 patients hospitalized in the period January 1, 2021, to March 31, 2021, with PCR-confirmed SARS-CoV-2 acute respiratory infection in two university and five rural hospitals were included in the study. After exclusion of patients with an unknown outcome, a total of 790 patients entered the final analysis. The effects of different treatments were assessed in this cohort by means of propensity score matching. RESULTS: Of the 790 patients, 282 patients died in the hospital; 37.7% were male and 33.3% were female. Age, sex, state of the disease, pneumonia, therapy, and several comorbidities were matched to simulate a case-control study. For anticoagulation treatment, 233 cases (full-dose) vs. 233 controls (prophylactic dose) were matched. The difference in mortality was significant in 16 of the 50 runs. For the treatment with isoprinosine, ivermectin, and vitamin D, none of the 50 runs led to a significant difference in hospital mortality. CONCLUSION: Prophylactic-dose anticoagulation treatment in our study was found to be beneficial in comparison with the full dose. Supplementation with vitamin D did not show any meaningful benefit in terms of lowering the hospital mortality. Neither ivermectin nor, isoprinosine was found to significantly decrease hospital mortality.

The Use of Antimicrobial Drug in Patients During the COVID-19 Pandemic: A Meta-Analysis.

Objective: To analyze the use of antimicrobial drugs in patients during the COVID-19 pandemic. Methods: We searched for literature about antimicrobial treatment in COVID-19 patients through the Cochrane Library, Embase, PubMed, the Chinese biomedical literature database, CNKI, the Chinese journal full-text database, Wanfang, and Vipu. The quality evaluation of the literature was performed by Jadad's quality score. Results: A total of three articles reported on ivermectin treatment in patients with COVID-19, and the Meta-analysis showed no clinical and statistical heterogeneity among the studies (I2 = 15%, P = .31), a fixed effect model was used to incorporate effect sizes. The clinical effect of the observed group was not different from the control group (P = .16). None of the three ivermectin articles with clinical effect as the effect indicator showed a significant difference (P > .05), suggesting no publication bias. A total of four publications reported the treatment with azithromycin in patients with COVID-19, and the Meta-analysis showed no clinical and statistical heterogeneity between the studies (I2 = 0%, P = .88), using a fixed-effect model to incorporate the effect sizes. The clinical effect of the observed group was not different from the control group (P = .57). None of the four azithromycin articles with a clinical effect as the effect index was statistically significant (P > .05), suggesting no publication bias. Conclusion: During the COVID-19 pandemic, the patient's use of antibiotics does not significantly improve clinical efficacy, so antibiotic use is recommended only for patients with complicated bacterial infections.

Pan-American Guidelines for the treatment of SARS-CoV-2/COVID-19: a joint evidence-based guideline of the Brazilian Society of Infectious Diseases (SBI) and the Pan-American Association of Infectious Diseases (API).

BACKGROUND: Since the beginning of the COVID-19 pandemic, therapeutic options for treating COVID-19 have been investigated at different stages of clinical manifestations. Considering the particular impact of COVID-19 in the Americas, this document aims to present recommendations for the pharmacological treatment of COVID-19 specific to this population. METHODS: Fifteen experts, members of the Brazilian Society of Infectious Diseases (SBI) and the Pan-American Association of Infectious Diseases (API) make up the panel responsible for developing this guideline. Questions were formulated regarding prophylaxis and treatment of COVID-19 in outpatient and inpatient settings. The outcomes considered in decision-making were mortality, hospitalisation, need for mechanical ventilation, symptomatic COVID-19 episodes, and adverse events. In addition, a systematic review of randomised controlled trials was conducted. The quality of evidence assessment and guideline development process followed the GRADE system. RESULTS: Nine technologies were evaluated, and ten recommendations were made, including the use of tixagevimab + cilgavimab in the prophylaxis of COVID-19, tixagevimab + cilgavimab, molnupiravir, nirmatrelvir + ritonavir, and remdesivir in the treatment of outpatients, and remdesivir, baricitinib, and tocilizumab in the treatment of hospitalised patients with severe COVID-19. The use of hydroxychloroquine or chloroquine and ivermectin was discouraged. CONCLUSION: This guideline provides recommendations for treating patients in the Americas following the principles of evidence-based medicine. The recommendations present a set of drugs that have proven effective in the prophylaxis and treatment of COVID-19, emphasising the strong recommendation for the use of nirmatrelvir/ritonavir in outpatients as the lack of benefit from the use of hydroxychloroquine and ivermectin.

In-feed emamectin benzoate abuse affects the biological responses and erythrocytes of Nile tilapia Oreochromis niloticus.

In aquaculture, drugs are often abused to accomplish disease control without considering the negative effects on fish health. This study aimed at elucidating the pernicious effects of in-feed antiparasitic drug emamectin benzoate (EB) abuse on the haemato-biochemistry and erythro-morphometry of healthy Nile tilapia Oreochromis niloticus. The fish were fed EB at 50 µg (1×) and 150 µg/kg biomass/d (3×) for 14 d as against the recommended 7 d and periodically assessed the blood parameters. A significant dose- and time-dependent reduction in feed intake, survival, total erythrocytes (TEC), monocytes (MC), hemoglobin (Hb), hematocrit (Ht) and mean corpuscular Hb concentration were noted. The total leukocytes (TLC), thrombocytes (TC), lymphocytes (LC) and neutrophils (NC) markedly augmented. The EB-dosing altered the fish physiology by enhancing the glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and creatinine and reducing the calcium, chloride and acetylcholinesterase (AChE) levels dose-dependently. The fish recovered within 4 weeks in the 1× group post-dosing but persevered in the overdosed group. The erythro-cellular and nuclear dimensions were reduced with the increase in dose and normalized after the cessation of dosing, except for nuclear volume. The erythro-morphological alterations were more prominent in the overdosed group. The results implied the pernicious effect of oral EB medication on the biological responses of fish if abused.

In Vitro Filaricidal Properties of Hydro-Methanolic Extracts of Powdery Fractions of Khaya senegalensis (Meliaceae) on Onchocerca ochengi.

PURPOSE: Onchocerciasis is a neglected tropical disease that remains endemic in sub-Saharan African countries. Unfortunately, only a few microfilaricidal agents have been approved so far. This study aimed to assess the in vitro macro and microfilaricidal potentialities of the hydro-methanolic extracts of the different powdery fractions of Khaya senegalensis against Onchocerca ochengi. METHODS: Adult male worms and microfilariae (mf) of O. ochengi were isolated from cowhides in Ngaoundere II, Cameroon. Parasites were incubated for 4 h (mf) or 48 h (adult worms) in RPMI-1640 medium in the presence or absence of ivermectin, flubendazole, or hydro-methanolic extracts of different plant powdery fractions obtained by controlled differential sieving. The filaricidal effect was evaluated using motility (mfs) and mortality tests (worms) and oxidative stress parameters. Cytotoxicity and acute toxicity tests were performed on monkey-derived kidney cell lines (LLC-MK2) and Swiss albino mice, respectively, and selectivity indexes were determined. Phytochemical screening was also carried out using high-performance liquid chromatography/UV (HPLC/UV), molecular networking, and through quantification of phenolic contents. RESULTS: The hydro-methanolic extracts of 0-63 µm fractions from leaves and barks exhibited the strongest macrofilaricidal activities with lethal concentrations 50 of 162.4 and 208.8 µg/mL respectively versus 22.78 µg/mL for flubendazole. These two fractions also showed the fastest microfilaricidal activities (T1/2 of 1 h), although it was low when compared to ivermectin (T1/2 < 1 h). Their macrofilaricidal effects were accompanied by a significant inhibition of nitric oxide secretion and a significant increase of glutathione and catalase activity compared to the untreated group. However, no effect was found on superoxide dismutase activity, the GABAergic and glutamatergic receptors. Although neither extract was toxic to Swiss mice until a dose of 2000 mg/kg body weight, the 0-63 µm leaf fraction hydro-methanolic extract was selectively more effective on worms than bark extract (SI = 1.28 versus 0.34). Both extracts were found to contain some flavonoids including procyanidin-, rutin-, myricetin-, and naringenin derivatives as well as new unknown compounds. However, the total polyphenol, flavonoid and tannin contents of the leaf extract were significantly greater (P < 0.05) than that of the bark extract. CONCLUSION: These results support the anti-filarial effect of K. senegalensis leaves and highlight stress oxidative markers as new therapeutic targets in O. ochengi. Further, in vivo experiments are required in understanding their anti-parasitic properties, and testing combinations of fine fractions.

Vitamins E and A increase the passing of the P-gp substrate ivermectin into the brain in mice.

This study aimed to determine the effect of administration of oral vitamins A and E at different doses on plasma and brain concentrations of ivermectin in mice. The study was carried out on 174 Swiss Albino male mice aged 8-10 weeks. After leaving six mice for method validation, the remaining mice were randomly divided into seven groups with equal numbers of animals. Mice received ivermectin (0.2 mg/kg, subcutaneous) alone and in combination with low (vitamin A: 4000 IU/kg; vitamin E: 35 mg/kg) and high (vitamin A: 30 000 IU/kg; vitamin E: 500 mg/kg) oral doses of vitamins A and E. The plasma and brain concentrations of ivermectin were measured using high-performance liquid chromatography-fluorescence detector. We determined that high doses of vitamins A and E and their combinations increased the passing ratio of ivermectin into the brain significantly. The high-dose vitamin E and the combination of high-concentration vitamins E and A significantly increased the plasma concentration of ivermectin (P < 0.05). The high-dose vitamins E and A and their high-dose combination increased the brain concentration of ivermectin by 3, 2, and 2.7 times, respectively. This research is the first in vivo study to determine the interaction between P-gp substrates and vitamins E and A.

Evaluation of therapeutic potential of ivermectin against complete Freund's adjuvant-induced arthritis in rats: Involvement of inflammatory mediators.

Rheumatoid arthritis is a chronic systemic inflammatory disease with genetic manifestations. According to recently published case reports, patients taking corticosteroid medication for the management of rheumatoid arthritis develop strongloidiasis and are at high risk of developing associated infections. This study explored the antiarthritic role of ivermectin, a drug used in the treatment of strongyloides and to compare its results with dexamethasone. Thirty-two male Wistar rats were randomly divided into four groups: control, diseased, dexamethasone, and ivermectin groups. Rheumatoid arthritis in all rats except the control group was induced by using complete Freund's adjuvant. After 7 days of rheumatoid arthritis induction, animals were treated with dexamethasone 5 mg/kg and ivermectin 6 mg/kg. Body weight, visual arthritic score, total leukocyte count, differential leukocyte count, proinflammatory genes, and histopathological findings were used to assess the effects of ivermectin on rheumatoid arthritis. Treatment with ivermectin showed a significant reduction in inflammatory cells levels, body weight, and visual arthritic score, indicating an improvement in the degree of inflammation as compared with the diseased group. Treatment with ivermectin and dexamethasone significantly reduced the augmentation in the mRNA expression levels of IL-17, TLR-2, TNF, and NF-κB as a result of arthritic development. Ivermectin treatment also showed a significant reduction in the severity of inflammation and destruction of joints and showed comparable effects to dexamethasone, a corticosteroid used for the treatment of rheumatoid arthritis. Ivermectin has significant antiarthritic properties and can be a novel treatment agent for the management of rheumatoid arthritis patients suffering from strongyloidiasis.

Selenium in the Prevention of SARS-CoV-2 and Other Viruses.

The rapid spread of new pathogens (SARS-CoV-2 virus) that negatively affect the human body has huge consequences for the global public health system and the development of the global economy. Appropriate implementation of new safety regulations will improve the functioning of the current model supervising the inhibition of the spread of COVID-19 disease. Compliance with all these standards will have a key impact on the health behavior of individual social groups. There have been demonstrably effective treatments that proved to be effective but were rapidly dismissed for unknown reasons, such as ivermectin and hydroxychloroquine. Various measures are used in the world to help inhibit its development. The properties of this element provide hope in preventing the development of the SARS-CoV-2 virus. The aim of this review is to synthesize the latest literature data and to present the effect of sodium selenite in reducing the incidence of COVID-19 disease.

Essential Oils against Sarcoptes scabiei.

Herbal remedia are widely employed in folk medicine, and have been more and more often studied and considered in the treatment of several infections. Sarcoptic mange (scabies, when referring to human patients) is a highly contagious skin disease caused by Sarcoptes scabiei (sarcoptiformes, Sarcoptinae), an astigmatid mite which burrows into the epidermis, actively penetrating the stratum corneum. This parasitosis negatively affects livestock productions and represents a constraint on animal and human health. The treatment relies on permethrine and ivermectine but, since these molecules do not have ovicidal action, more than a single dose should be administered. Toxicity, the possible onset of parasite resistance, the presence of residues in meat and other animal products and environmental contamination are the major constraints. These shortcomings could be reduced by the use of plant extracts that have been in vitro or in vivo checked against these mites, sometimes with promising results. The aim of the present study was to review the literature dealing with the treatment of both scabies and sarcoptic mange by plant-derived agents, notably essential oils.

Modulation of P2X4 receptor activity by ivermectin and 5-BDBD has no effect on the development of ARPKD in PCK rats.

Autosomal recessive polycystic kidney disease (ARPKD) is an inherited pathology caused mainly by mutations of the polycystic kidney and hepatic disease 1 (PKHD1) gene, which usually leads to end-stage renal disease. Previous studies suggested that the P2X purinoreceptor 4 (P2X4 R) may play an important role in the progression of ARPKD. To test this hypothesis, we assessed the chronic effects of ivermectin (P2X4 R allosteric modulator) and 5-BDBD (P2X4 R antagonist) on the development of ARPKD in PCK/CrljCrl-Pkhd1pck/CRL (PCK) rats. Our data indicated that activation of ATP-mediated P2X4 R signaling with ivermectin for 6 weeks in high dose (50 mg/L; water supplementation) decreased the total body weight of PCK rats while the heart and kidney weight remained unaffected. Smaller doses of ivermectin (0.5 or 5 mg/L, 6 weeks) or the inhibition of P2X4 R signaling with 5-BDBD (18 mg/kg/day, food supplement for 8 weeks) showed no effect on electrolyte balance or the basic physiological parameters. Furthermore, cystic index analysis for kidneys and liver revealed no effect of smaller doses of ivermectin (0.5 or 5 mg/L) and 5-BDBD on the cyst development of PCK rats. We observed a slight increase in the cystic liver index on high ivermectin dose, possibly due to the cytotoxicity of the drug. In conclusion, this study revealed that pharmacological modulation of P2X4 R by ivermectin or 5-BDBD does not affect the development of ARPKD in PCK rats, which may provide insights for future studies on investigating the therapeutic potential of adenosine triphosphate (ATP)-P2 signaling in PKD diseases.

Comparative efficacy and safety of pharmacological interventions for severe COVID-19 patients: An updated network meta-analysis of 48 randomized controlled trials.

BACKGROUND: To date, there has been little agreement on what drug is the "best" drug for treating severe COVID-19 patients. This study aimed to assess the efficacy and safety of different medications available at present for severe COVID-19. METHODS: We searched databases for randomized controlled trials (RCTs) published up to February 28, 2022, with no language restrictions, of medications recommended for patients (aged 16 years or older) with severe COVID-19 infection. We extracted data on trials and patient characteristics, and the following primary outcomes: all-cause mortality (ACM), and treatment-emergent adverse events (TEAEs). RESULTS: We identified 4021 abstracts and of these included 48 RCTs comprising 9147 participants through database searches and other sources. For decrease in ACM, we found that ivermectin/doxycycline, C-IVIG (i.e., a hyperimmune anti-COVID-19 intravenous immunoglobulin), methylprednisolone, interferon-beta/standard-of-care (SOC), interferon-beta-1b, convalescent plasma, remdesivir, lopinavir/ritonavir, immunoglobulin gamma, high dosage sarilumab (HS), auxora, and imatinib were effective when compared with placebo or SOC group. We found that colchicine and interferon-beta/SOC were only associated with the TEAEs of severe COVID-19 patients. CONCLUSION: This study suggested that ivermectin/doxycycline, C-IVIG, methylprednisolone, interferon-beta/SOC, interferon-beta-1b, convalescent plasma (CP), remdesivir, lopinavir/ritonavir, immunoglobulin gamma, HS, auxora, and imatinib were efficacious for treating severe COVID-19 patients. We found that most medications were safe in treating severe COVID-19. More large-scale RCTs are still needed to confirm the results of this study.

In vitro and in vivo anthelmintic properties of Caesalpinia coriaria fruits against Haemonchus contortus.

The purpose of the present study was to assay the in vitro and in vivo anthelmintic activity (AA) of Caesalpinia coriaria (Cc) mature fruits against the nematode Haemonchus contortus (Hc). The Hc infective larvae were used to assess the in vitro AA through larval mortality assay. The exposure of larvae to the different treatments was performed in 96-well microtitration plates. The treatments were as follows: hydroalcoholic extract (HA-E, at 25-100 mg/mL), aqueous fraction (Aq-F, at 12.5-50 mg/mL), organic fraction (EtOAc-F at 12.5-50 mg/mL), compounds (1, methyl gallate and 2, gallic acid at 1.25-10 mg/mL), positive control (ivermectin at 5 mg/mL) and two negative controls (distilled water and 4% methanol). After exposure, dead and live larvae were quantified and results were compared to their controls. The in vivo assay was carried out by a faecal egg count reduction test (FECRT); artificially infected goat kids (F1: Boer x Nubia) were treated with Cc ground dried fruits to assess the AA. The treatments were established as follows: G1-untreated goats (negative control), G2-goats dewormed with ivermectin (positive control), G3-goats fed with Cc mature fruits (10% of their diet). Results in both in vitro and in vivo assays were analysed using an ANOVA through random design, applying a general linear model and mixed models. The in vitro results showed an evident larvicidal effect of the HA-E, EtOAc-F from Cc, indicating that the compound responsible for the AA was gallic acid. The results of the in vivo study corroborated the anthelmintic properties of Cc, reaching 78.6% reduction in the elimination of Hc eggs per gram of faeces. This plant represents a potential natural anthelmintic for the control of haemonchosis in goats under grazing conditions. Future studies should standardise the Cc extract or dried fruits for use in the management of nematodiasis in goat herds.

In search for a panacea for coronavirus disease-19: Analysis of ongoing clinical trials for the management of coronavirus disease-19 pandemic in India.

OBJECTIVE: To analyze the clinical trials that are registered on the Clinical Trial Registry of India (CTRI) portal for a year, for the treatment, prevention, and supportive therapy of coronavirus disease-19 (COVID-19). MATERIALS AND METHODS: All the trials registered on CTRI (since January 2020 till January 2021) for therapeutic, preventive, and supportive interventions for COVID-19 were searched with the keywords "Coronavirus," "COVID-19," "SARS-COV-2," and "2019-nCoV". These registered studies were analyzed as follows: Trials under different systems of Medicine-Allopathy/Homeopathy/Ayurveda/Unani/Yoga/Naturopathy. The Allopathy trials were further analyzed in detail: Intervention, design, comparator, number of subjects, duration, and approvals taken. RESULTS: A total of 1597 records were found. After excluding the overlaps, behavioral and other studies conducted to understand the diagnosis, epidemiology, a total of 419 registered studies were included for further analysis. Out of these 419 studies, 166 (39.6%) were in Ayurveda, 154 (36.7%) in Allopathy, 33 (7.8%) in Homeopathy, 30 (7%) in Unani/Siddha, 18 (4.3%) in Yoga and Naturopathy and 18 (4.3%) in Nutraceuticals. A total of 264 interventions had been registered in 419 clinical trials. Sixty-seven interventions were being studied under allopathy in 154 studies. Same product was being evaluated in differently designed protocols with different endpoints. Maximum number of trials and subjects were for Hydroxychloroquine 25 (17,998), Ivermectin 11 (2820), Convalescent Plasma 11 (3982), Remdesivir 8 (3725), Tocilizumab 6 (884), and Azithromycin 6 (582). CONCLUSIONS: In response to the COVID-19 pandemic, Indian researchers came forward from all the systems of medicine to evaluate interventions for prophylaxis or treatment of the disease. The involvement of AYUSH systems of medicine was specifically more in this regard. A wide variation and heterogeneity in doses and outcomes were observed in trial designs which might make it difficult to generalize the study results when they are made available. Urgent analyses of studies involving interventions on the treatment advisory of the Government may help the healthcare providers take more informed decisions for managing COVID-19 patients in India.

Non-target toxic effects of avermectin on carp spleen involve oxidative stress, inflammation, and apoptosis.

Avermectin is one of the most widely used pesticides, but its toxicity to non-target organisms, especially aquatic organisms, has been ignored. Therefore, an acute spleen injury model of avermectin in carp was established to assess the non-target toxicity of avermectin to carp. In this study, 3.005 µg/L and 12.02 µg/L were set as the low and high dose groups of avermectin, respectively, and a four days acute exposure experiment was conducted. Pathological structure observation showed that avermectin damaged spleen tissue structure and produced inflammatory cell infiltration. Biochemical analysis showed that avermectin significantly reduced the activities of antioxidant enzymes CAT, SOD, and GSH-px, but increased the content of MDA, a marker of oxidative damage. Avermectin exposure also significantly increased the transcription levels of inflammatory cytokines such as IL-1ß, IL-6, TNF-α, and INOS, and also significantly enhanced the activity of the inflammatory mediator iNOS, but suppressed the transcription levels of anti-inflammatory factors TGF-ß1 and IL-10. In addition, TUNEL detected that the apoptosis rate increased significantly with the increase of avermectin dosage, and the transcription levels of apoptosis-related genes BAX, P53, and Caspase 3/9 also increased in a dose-dependent manner. This study is preliminary evidence that avermectin induces spleen injury in carp through oxidative stress, inflammation, and apoptosis, which has important implications for subsequent studies on the effects of avermectin on non-target organisms.

The effect of Spondias mombin L. against Strongyloides venezuelensis: An in vitro approach.

Strongyloidiasis is a neglected tropical disease mainly caused by the nematode parasite Strongyloides stercoralis. Current treatment consists in the administration of ivermectin or, alternatively, albendazole (or analogues). Concerns regarding these drugs' irregular cure rates and side effects, raise a need for therapeutic alternatives. In this study, we tested the in vitro effect of Spondias mombin L. ethanolic extract against the laboratory model for strongyloidiasis, Strongyloides venezuelensis. The ethanolic extract was further fractionated and each fraction was also tested. Tested fractions were analyzed through thin layer chromatography and gas chromatography (GC/MS). Our results showed that S. mombin extract and fractions had a better in vitro effect than ivermectin, particularly fraction 4 which showed the better results causing 100% mortality in 4 h after exposure to an extract concentration of 400 µg/mL of RPMI medium and caused 100% mortality 12 h after exposure to an extract concentration of 50 µg/mL. Scanning electron microscopy showed that this fraction caused both wrinkling and peeling of the parasites cuticle, whilst ivermectin only caused wrinkling. GC/MS showed a high percentage of monoaromatic phenolic lipids (3-R phenol and 3-R1 phenol), which were likely responsible for the anti-Strongyloides effect. The use of polyvinylpyrrolidone reduced the efficiency, thus raising a need for alertness when using this excipient. Our results suggest that S. mombin is a potential source of compounds that could be used for stongyloidiasis treatment.