Pharmacokinetics of recombinant human annexin A5 (SY-005) in patients with severe COVID-19.

Objective: Annexin A5 is a phosphatidylserine binding protein with anti-inflammatory, anticoagulant and anti-apoptotic properties. Preclinical studies have shown that annexin A5 inhibits pro-inflammatory responses and improves organ function and survival in rodent models of sepsis. This clinical trial aimed to evaluate the pharmacokinetic (PK) properties of the recombinant human annexin A5 (SY-005) in severe COVID-19. Methods: This was a pilot randomized, double-blind, placebo-controlled trial. Severe COVID-19 patients were randomly assigned to receive intravenous 50 µg/kg (low dose, n = 3), 100 µg/kg (high dose, n = 5) of SY-005 or placebo (n = 5) every 12 h for 7 days. Plasma SY-005 levels were assessed using enzyme-linked immunosorbent assay (ELISA) and the PK parameters were determined using non-compartmental analysis. Results: All patients treated with SY-005 had a normal baseline estimated glomerular filtration rate (eGFR, 104-125 mL/min/1.73 m2). Both low and high doses of SY-005 were cleared within 6 h after intravenous administration. Plasma maximum concentrations (Cmax), half-life, clearance and volume distribution of low and high doses of SY-005 were 402.4 and 848.9 ng/mL, 0.92 and 0.96 h, 7.52 and 15.19 L/h, and 9.98 and 20.79 L, respectively. Daily pre-dose circulating annexin A5 levels were not significantly different when SY-005 was administered at the low or the high dose 12-h intervals. There was no significant effect on activated partial thromboplastin time (aPTT) or INR (international normalized ratio of prothrombin time) during 7 days of SY-005 treatment. Conclusion: SY-005 doses of 50 and 100 µg/kg were detectable and subsequently cleared from the plasma in severe COVID-19 patients with normal baseline renal function. There was no significant plasma SY-005 accumulation 6 h after drug administration and coagulation was not altered during 7 days of treatment. Clinical trials Registration: This study was registered with ClinicalTrials.gov (NCT04748757, first posted on 10 February 2021).

Characterization of Cellulose-Degrading Bacteria Isolated from Soil and the Optimization of Their Culture Conditions for Cellulase Production.

The characterization of bacteria with hydrolytic potential significantly contributes to the industries. Six cellulose-degrading bacteria were isolated from mixture soil samples collected at Kingfisher Lake and the University of Manitoba campus by Congo red method using carboxymethyl cellulose agar medium and identified as Paenarthrobacter sp. MKAL1, Hymenobacter sp. MKAL2, Mycobacterium sp. MKAL3, Stenotrophomonas sp. MKAL4, Chryseobacterium sp. MKAL5, and Bacillus sp. MKAL6. Their cellulase production was optimized by controlling different environmental and nutritional factors such as pH, temperature, incubation period, substrate concentration, nitrogen, and carbon sources using the dinitrosalicylic acid and response surface methods. Except for Paenarthrobacter sp. MKAL1, all strains are motile. Only Bacillus sp. MKAL6 was non-salt-tolerant and showed gelatinase activity. Sucrose enhanced higher cellulase activity of 78.87 ± 4.71 to 190.30 ± 6.42 U/mL in these strains at their optimum pH (5-6) and temperature (35-40 °C). The molecular weights of these cellulases were about 25 kDa. These bacterial strains could be promising biocatalysts for converting cellulose into glucose for industrial purposes.

Pharmacological evidence of Vitex thyrsiflora, Entandrophragma cylindricum, and Anonidium mannii used for the management of inflammation in Cameroon.

Background Inflammation is the most common health problem faced in life relating to a vast number of diseases. The present study evaluated the pharmacological effect of three plants (Vitex thyrsiflora, Entandrophragma cylindricum, and Anonidium mannii) commonly used in the Cameroon pharmacopeia for the management of inflammatory response. Methods The pharmacological effect was characterized by the antioxidant capacity, anti-inflammatory, analgesic, and antipyretic properties of the ethanol extracts of the three plants. Antioxidant capacity was determined using total phenolic content, total flavonoid content, hydrogen peroxide, ferric reducing antioxidant power (FRAP), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) radical scavenging assays. Anti-inflammatory activity was evaluated in vitro by protein denaturation and hypotonic-induced hemolysis methods and in vivo by carrageenan paw edema method. Analgesic and antipyretic activities were studied in vivo using acetic acid-induced writhing and brewer's yeast-induced hyperpyrexia models. Results All selected extracts showed high phenolic (15.93-64.45 mgCAE/g) and flavonoid (336.03-1053.48 mgCAE/g) contents and high ferric reducing power (288.75-364.91 mgCAE/g). These extracts exhibited good DPPH (IC50 = 0.30-1.65 µg/mL), ABTS (IC50 = 0.52-1.90 µg/mL), and H2O2 (IC50 = 1.40-3.55 µg/mL) radical scavenging activities. All extracts inhibited protein denaturation (6.79-82.27%) and protected the erythrocyte membrane from lysis induced by hypotonic solution (18.90-88.00%). The extracts significantly reduced dose-dependent paw edema (p < 0.05), fever, and abdominal writhing (p < 0.001) especially at 400 mg/kg. Conclusions All extracts exhibited interesting antioxidant properties, as well as significant anti-inflammatory, analgesic, and antipyretic effects.

Antimycobacterial potency and cytotoxicity study of three medicinal plants.

OBJECTIVE/BACKGROUND: Mycobacterial infections including tuberculosis, leprosy, and buruli ulcer are among the most prevalent, debilitating, and deadly tropical diseases, especially in Sub-Saharan Africa. The development of drug resistance to the currently available drugs and the poor compliance emphasize the need for new chemotherapeutic agents. This study was designed to evaluate the in vitro activity of Cleistopholis patens, Annona reticulata, and Greenwayodendron suaveolens against Mycobacterium smegmatis. The safety on normal liver cells was also assessed. METHODS: The crude extracts, fractions, and subfractions were tested against M. smegmatis and for cell cytotoxicity on WRL-68, normal human hepatocyte using microdilution resazurin-based assays. The phytochemical screening was performed using standard methods. RESULTS: Most of the extracts, fractions, and subfractions inhibited the growth of M. smegmatis with minimum inhibitory concentration (MIC) values ranging from 6.25µg/mL to 125µg/mL. The subfractions P12 and P29 from G. suaveolens twig were more potent with MIC values of 6.25µg/mL and 25µg/mL, respectively. Fruit crude extract and root CH2Cl2 fraction from A. reticulata also showed activity with MIC values of 50µg/mL and 25µg/mL, respectively. Crude extracts from the twig and stem bark of C. patens displayed inhibition at MIC values of 125µg/mL and 100µg/mL, respectively. Majority of active extracts showed no cell cytotoxicity, except the extract from C. patens with IC50 ranging from 41.40µg/mL to 93.78µg/mL. The chemical investigation of the promising extracts revealed the presence of phenols, alkaloids, glycosides, triterpenes, and acetogenins. CONCLUSION: The results achieved from this preliminary antimycobacterial drug discovery study supported the traditional claims of C. patens, A. reticulata, and G. suaveolens in the treatment of mycobacterial infections. Meanwhile, further fractionation is required to characterize the active ingredients.

Antibacterial and Antioxidant Properties of the Methanolic Extract of the Stem Bark of Pteleopsis hylodendron (Combretaceae).

Pteleopsis hylodendron (Combretaceae) is used in Cameroon and West Africa folk medicine for the treatment of various microbial infections (measles, chickenpox, and sexually transmitted diseases). The antibacterial properties of the methanolic extract and fractions from stem bark of Pteleopsis hylodendron were tested against three Gram-positive bacteria and eight Gram-negative bacteria using Agar-well diffusion and Broth microdilution methods. Antioxidant activities of the crude extract and fractions were investigated by DPPH radical scavenging activity and ß-carotene-linoleic acid assays. The methanolic extract and some fractions exhibited antibacterial activities that varied between the bacterial species (ID = 0.00-25.00 mm; MIC = 781-12500 µg/mL and 0.24-1000 µg/mL). The activity of the crude extract is, however, very weak compared to the reference antibiotics (MIC = 0.125-128 µg/mL). Two fractions (F(E) and F(F)) showed significant activity (MIC = 0.97 µg/mL) while S. aureus ATCC 25922 was almost resistant to all the tested fractions. In addition, the crude extract and some fractions showed good antioxidant potential with inhibition values ranging from 17.53 to 98.79%. These results provide promising baseline information for the potential use of this plant as well as some of the fractions in the treatment of infectious diseases and oxidative stress.